@article {pmid41170438,
year = {2025},
author = {Zhang, X and Huang, X and Chang, M},
title = {Association between periodontal disease and Alzheimer's disease: a scoping review.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1588008},
pmid = {41170438},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, with mild cognitive impairment (MCI) as its early reversible stage. Periodontal disease (PD) is a chronic inflammatory condition associated with systemic diseases. Recent studies suggest a potential link between PD and AD/MCI. This scoping review evaluates the existing evidence on the association between PD and AD and explores possible mechanisms.

METHODS: A literature search was conducted in PubMed, Embase, and Cochrane databases (September 2025), covering studies from 2004 to 2025. Human clinical studies, animal models, and in vitro experiments were included, while reviews were excluded. Two independent researchers performed study selection, data extraction, and quality assessment.

RESULTS: A total of 52 studies were included after screening 1,369 records. Among them, 25 clinical studies examined the PD-AD association, including case-control, cohort, and cross-sectional studies. Additionally, 24 studies investigated underlying mechanisms, and 3 animal studies assessed PD-related interventions for AD. Evidence suggests PD increases the risk of AD and accelerates cognitive decline. Potential mechanisms include amyloid-β (Aβ) and tau protein aggregation, neuroinflammation triggered by Porphyromonas gingivalis (Pg) infection, and gut-brain axis dysregulation. Periodontal treatment and probiotics may have protective effects against AD-related pathology.

CONCLUSIONS: PD may be a modifiable risk factor for AD, and periodontal interventions could contribute to AD prevention and management. Further clinical studies are needed to confirm the therapeutic potential of targeting oral microbiota in AD.},
}

@article {pmid41170189,
year = {2025},
author = {Pakdel, M and Asle-Rousta, M and Sadegh, M and Eidi, A},
title = {Linalool vs linalool-loaded chitosan nanoparticles in an Aβ-induced rat model of Alzheimer's disease: A molecular, biochemical, histological, and behavioral study.},
journal = {Iranian journal of basic medical sciences},
volume = {28},
number = {11},
pages = {1495-1504},
pmid = {41170189},
issn = {2008-3866},
abstract = {OBJECTIVES: Recent studies have increasingly focused on applying nanotechnology to treat neurodegenerative diseases. In this study, we compared the effects of the monoterpene linalool and linalool-loaded chitosan nanoparticles on key pathological features of Alzheimer's disease (AD), including oxidative stress, neuroinflammation, neuronal death, amyloid plaque deposition, alterations in tryptophan metabolism, and memory deficit in a rat model of AD.

MATERIALS AND METHODS: An intracerebroventricular injection of Aβ42 (10 µg) was used to induce the AD model. Linalool (25 mg/kg) and nano-linalool (25 mg/kg) were administered orally once daily for 30 consecutive days.

RESULTS: Both linalool and nano-linalool significantly reduced malondialdehyde levels and enhanced superoxide dismutase activity in the hippocampus. They also decreased the mRNA levels of monocyte chemoattractant protein-1, inhibited the up-regulation of beta-secretase, reduced amyloid plaque deposition, and attenuated pyramidal neuron death in the CA1 region. Additionally, treatment with both compounds down-regulated indoleamine 2,3-dioxygenase, lowered kynurenine levels, and increased serotonin concentrations in the hippocampus. Although both treatments improved learning and spatial memory in Aβ-injected rats, nano-linalool's effectiveness was more significant than that of linalool in modulating the molecular, biochemical, and histological parameters.

CONCLUSION: Encapsulating linalool in chitosan nanoparticles enhances its effectiveness in improving molecular, biochemical, and histological changes in the hippocampus of rat models of AD.},
}

@article {pmid41169672,
year = {2025},
author = {Teipel, S and Baena, A and He, B and Martinez, L and Aguillon, D and Quiroz, YT and Grazia, A},
title = {Thalamus not basal forebrain is atrophied in non-demented PSEN1 E280A carriers.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70206},
pmid = {41169672},
issn = {2352-8729},
abstract = {INTRODUCTION: A previous study of non-demented presenilin-1 (PSEN1) E280A carriers found basal forebrain and hippocampus, but not the thalamus, to be preserved. This study tested the hypothesis of preservation in an independent PSEN1 E280A sample and explored associations with amyloid and tau pathology.

METHODS: We analyzed multimodal neuroimaging data from 57 individuals in the Colombia-Boston (COLBOS) cohort (non-carriers: 30 and carriers: 27). We used Bayesian multiple regression with priors to test our hypothesis.

RESULTS: Carrier status had no effect on basal forebrain (Bayes factor [BF10] = 0.54) and hippocampal volume (BF10 = 1.05). However, smaller volumes were found in the thalamus of mutation carriers (BF10 = 8.74). We found evidence against an effect of amyloid and tau pathology on basal forebrain, but evidence for an effect on the thalamus.

DISCUSSION: Our results support the preservation of the cholinergic basal forebrain and hippocampus, while highlighting early thalamic involvement in PSEN1 E280A carriers. This has implications for future selection of treatment targets.

HIGHLIGHTS: Basal forebrain volume preserved in non-demented presenilin-1 (PSEN1) E280A carriers.Hippocampal volume preserved in non-demented PSEN1 E280A carriers.Thalamic atrophy observed in non-demented PSEN1 E280A carriers.No link between amyloid/tau pathology and basal forebrain volume.Tau burden linked to hippocampal and thalamic volume loss.},
}

@article {pmid41169223,
year = {2025},
author = {Chen, Z and Wang, X and Wang, S and Wu, Z and Wang, H and Chiu, K and Zheng, X and So, KF},
title = {Lycium barbarum glycopeptide protects neurons from amyloid-beta toxicity.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00501},
pmid = {41169223},
issn = {1673-5374},
abstract = {Oligomeric amyloid-beta deposition within neurons and its associated neurotoxicity are among the most direct indicators of the onset of Alzheimer's disease. Investigations into strategies aimed at reducing amyloid-beta accumulation or promoting its clearance in neurons are currently being carried out. Lycium barbarum glycopeptide is rich in biologically active compounds and possesses antioxidant, anti-inflammatory, and neuroprotective properties. This study verified that the oligomer amyloid-beta1-42 induced toxic effects in mouse N2a neuroblastoma cells, resulting in elevated levels of reactive oxygen species and increased expression of the inflammatory enzyme inducible nitric oxide synthase. Lycium barbarum glycopeptide counteracted these effects by alleviating cell damage, enhancing cell viability, reducing the levels of reactive oxygen species and inducible nitric oxide synthase expression, and up-regulating the mRNA levels of antioxidant enzymes, including superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 4. Lycium barbarum glycopeptide also activated the phosphoinositide 3-kinase/Akt/p70S6K signaling pathway and promoted the expression of brain-derived neurotrophic factor, thus exerting neuroprotective effects. These findings indicate that Lycium barbarum glycopeptide may be a promising candidate for the treatment of Alzheimer's disease.},
}

@article {pmid41169221,
year = {2025},
author = {Zhang, Z and Deng, W and Hu, L and Hu, Y and Zhang, S and Xiong, Y and Liu, X and Yu, P and Yu, S and Yuan, L and Zhang, J},
title = {Zinc homeostasis imbalance: Potential therapeutic value in neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00632},
pmid = {41169221},
issn = {1673-5374},
abstract = {Zinc homeostasis genes are a general term for a family of genes responsible for regulating the concentration of intracellular and extracellular zinc ions, including the SLC39 (ZIP) family, the SLC30 (ZnT) family, and the metallothionein family. As an essential trace element, zinc is involved in biomolecular synthesis, energy metabolism, redox regulation, and gene expression. Recent studies have shown that abnormal expression of zinc homeostasis genes mediates neuronal apoptosis through multiple pathways, including oxidative stress and neuroinflammation. Imbalance in zinc homeostasis can result in the pathological development of various neurodegenerative disorders, including the deposition of amyloid-β in Alzheimer's disease and the aberrant aggregation of α-synuclein in Parkinson's disease. Therefore, regulating the expression of zinc homeostasis genes to restore normal zinc levels in vivo may be an effective strategy for treating neurodegenerative diseases. This review comprehensively summarizes the current status of research exploring zinc homeostasis genes across various family subtypes, as well as the altered expression of these genes in different neurodegenerative diseases and the underlying mechanisms. Finally, we propose zinc chelator supplementation as a novel interventional therapy for neurodegenerative diseases. This proposal includes an evaluation of the feasibility, safety, and limitations of this treatment, providing an innovative perspective for the clinical management of neurodegenerative diseases in the future.},
}

@article {pmid41169131,
year = {2025},
author = {Mikellides, G and Emam Jomeh, AA and Roy, EA and Kyriazis, M},
title = {Repetitive Transcranial Magnetic Stimulation in Dementia.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098392580251003064940},
pmid = {41169131},
issn = {1874-6128},
abstract = {Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuromodulatory technique that is increasingly being investigated for its therapeutic potential in cognitive impairment associated with dementia and Alzheimer's disease. This narrative review synthesizes and critically appraises the current evidence surrounding rTMS, with particular focus on clinical efficacy, neurobiological mechanisms, and emerging innovations. High-frequency stimulation over the Dorsolateral Prefrontal Cortex (DLPFC) has consistently demonstrated improvements in memory, executive function, and attention, likely mediated by enhanced synaptic plasticity, increased neurotrophic factor expression, and modulation of large-scale brain networks, such as the default mode and fronto-parietal networks. Recent high-quality studies have built upon earlier research to highlight the comparative efficacy of target-specific stimulation, including precuneus- and parietal-based protocols, as well as multi- site strategies that engage language and associative regions. It also examines the use of TMSEEG and DMN connectivity as predictors of treatment response, supporting a shift toward personalized, biomarker-guided rTMS paradigms. Moreover, the synergistic potential of combining rTMS with cognitive training and pharmacotherapy is explored as a promising avenue for multimodal treatment. While preliminary results are encouraging, heterogeneity in study design and stimulation parameters continues to limit the generalizability of the findings. Standardization of protocols, longterm efficacy validation, and large-scale clinical trials remain critical to translating rTMS into routine dementia care.},
}

@article {pmid41168999,
year = {2025},
author = {Zhang, J and He, Y and Yang, P and Zhang, H and Tong, Y and Jiang, L and Li, Z and Yan, M and Li, X and Yang, Q and Yang, J and Yuan, Z and Zhang, J and Cheng, J},
title = {Microglial Rack1 Deficiency Alleviates Alzheimer's Disease Pathology through Enhancing IGF1-Mediated Astrocytic Phagocytosis.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e15877},
doi = {10.1002/advs.202515877},
pmid = {41168999},
issn = {2198-3844},
support = {82071218//National Nature Science Foundation of China/ ; 82271237//National Nature Science Foundation of China/ ; 81930029//National Nature Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder. Microglia make significant contributions to neuroinflammation and the progression of AD. However, the regulatory role of microglial activation and the communication between microglia and astrocytes in AD are largely unknown. Here, it is found that Rack1 levels are elevated in microglia of patients with AD and AD model mice. The conditional knockout of Rack1 in microglia reduced Aβ aggregation, alleviated neuroinflammation, and rescued cognitive impairments in AD model mice. Mechanistically, the knockout of Rack1 in microglia decreased the number of microglia while increasing both the numbers and phagocytic activities of astrocytes by upregulating the levels of IGF1. The inhibition of IGF1R blocked microglial Rack1 deficiency-induced astrocyte proliferation and astrocyte-mediated phagocytosis both in vitro and in vivo. Collectively, the results demonstrated that microglial Rack1 contributes to AD pathology, at least partially through influencing IGF1-IGF1R signaling between microglia and astrocytes, thus providing a potential target for AD treatment.},
}

@article {pmid41167569,
year = {2025},
author = {Xiong, R and Liu, H and Zhang, S and Wang, L and Zhang, P and Wang, Y and Ou, X and Wu, A and Lai, X},
title = {Acorus tatarinowii Schott Attenuates Alzheimer's Disease via Neuronal Ferroptosis Inhibition:A Synergistic Network Pharmacology and Multi-Omics Profiling Study.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120829},
doi = {10.1016/j.jep.2025.120829},
pmid = {41167569},
issn = {1872-7573},
abstract = {The dried rhizome of Acorus tatarinowii Schott (ATR) is the most widely used traditional Chinese medicine for the treatment of dementia due to its effect of opening orifices and eliminating phlegm (Kai-Qiao-Huo-Tan in Chinese), reviving the mind and enhancing intelligence (Xing-Shen-Yi-Zhi in Chinese), but its mechanism remains not fully understood.

AIM OF THE STUDY: To reveal the mechanism of ATR in the treatment of Alzheimer's disease (AD), which is a major type of dementia.

MATERIALS AND METHODS: The effects of ATR on cognitive function and neuronal loss in APP/PS1 mice were evaluated by novel object recognition test, nesting test, hematoxylin-eosin staining and Nissl staining. The underlying mechanism were studied by serum metabolomics, transcriptomics, network pharmacology, RT-PCR, Western blot, immunofluorescence and immunohistochemistry.

RESULTS: ATR significantly improved cognitive function, neuronal loss, and altered lipid metabolism in APP/PS1 mice. In β-amyloid (Aβ)1-42 and ferric citrate (FC)-induced HT22 cells, ATR significantly improved the cell viability, reduced the intracellular free iron, reactive oxygen species and lipid peroxidation, and transcriptome analysis showed that the mechanism was related to ferroptosis and iron metabolism. Network pharmacology analysis indicated that ATR may regulate Nrf2 signaling. Both in vitro and in vivo results showed that ATR increased the mRNA and protein expression of Nrf2 and GPX4. ATR also reduced brain iron deposition, downregulated TFR1 and upregulated FPN1 expression in APP/PS1 mice.

CONCLUSIONS: ATR ameliorated AD by improving iron metabolism and inhibiting neuronal ferroptosis through activation of Nrf2/GPX4 axis, which provided modern medical evidence for the use of ATR to improve AD.},
}

@article {pmid41166911,
year = {2025},
author = {Barth, SW and Efferth, T},
title = {Network pharmacology to elucidate the role of phytotherapy in neurocognitive disorders.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {148},
number = {},
pages = {157031},
doi = {10.1016/j.phymed.2025.157031},
pmid = {41166911},
issn = {1618-095X},
abstract = {BACKGROUND: To date, there are no entirely satisfactory drugs available to treat neurocognitive disorders. In light of the increasing incidences of these disorders in societies with aging populations, there is an urgent need to further improve treatment options.

HYPOTHESIS: Phytotherapy modulates diseases and symptoms by addressing multiple rather than single targets. Therefore, phytotherapy might be suited to treat complex diseases such as neurocognitive disorders.

METHODS AND BACKGROUND: We performed a systematic review of the literature with defined search terms using the PubMed database. The search terms were: [(network pharmacology) OR (systems pharmacology) OR (microarray) OR (proteomic) OR (metabolomic) OR (transcriptomic) OR (RNA-seq)] AND [Alzheimer) OR (dementia)]. These search strings were connected with [(herbal) OR (botanical)] for polyherbal formulations and [(phytochemical) OR (natural product)] for single-herb preparations. Systems biology focuses on the human organism as dynamic networks that cooperate in an orchestrated manner in the healthy as well as in the diseased body. The diseasome concept integrates disease phenotypes with hierarchical networks across various biological levels-organ networks, cellular networks, and signaling networks. Network pharmacology aims to interfere with such networks to treat complex, multifactorial diseases. Diseases may be caused by exposure to external factors harmful to health (exposomes). Phytotherapy might beneficially influence diseasomes thus restoring disturbed networks. Here, the "phytome" which integrates herbal drug ingredients into the exposome may be a rich source with which to counteract diseased networks.

RESULTS: Our literature search identified 642 hits. The final number of papers included was 41. Using sophisticated animal models (transgenic mice, injection of amyloid β fragments or specific chemicals, surgical interventions) conditions have been generated that resemble Alzheimer's disease, vascular dementia, and other types of dementia. Brain tissues (mainly hippocampus and cortex), blood serum, urine, and feces were investigated using metabolomic, proteomic, and transcriptomic methods. In these experimental dementia models, specific signaling networks were reported to be affected: they regulate pathophysiological mechanisms of inflammation, signal processing and transmission, neuroplasticity, vascular function and blood, cellular integrity and metabolism as well as cellular redox balance. About two dozen polyherbal formulations (mainly derived from traditional Chinese medicine) were used for treatment in these models and partially or fully restored not only the diseased networks (diseasomes) but also the disease symptoms. Another dozen mono-herbal preparations were used to treat dementia in experimental models, and similar beneficial effects were observed.

CONCLUSION: The selected 41 papers from the literature provided a good basis for a detailed analysis of the role of network pharmacology in understanding the multimodal modes of action of herbal preparations in neurocognitive disorders. Complex signaling networks add valuable new information to classical pharmacology. The understanding of phytopharmaceuticals' modes of action underpin the necessity to expand the search from classic pharmacological models to complex network interactions.},
}

@article {pmid41166828,
year = {2025},
author = {Gomes, LS and Schüler, MCGM and Giannini, GB and Zapp, E and de Oliveira, AS and Nascimento, V},
title = {Multifunctional Carvacrol-based Organoselenium hybrids as anticholinesterase and antioxidant candidates for Alzheimer's therapy.},
journal = {Bioorganic & medicinal chemistry},
volume = {132},
number = {},
pages = {118447},
doi = {10.1016/j.bmc.2025.118447},
pmid = {41166828},
issn = {1464-3391},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Acetylcholinesterase (AChE) inhibition remains a validated approach for symptomatic management. Natural compounds such as carvacrol and selenium-based organochalcogenides are promising due to their antioxidant and neuroprotective properties.

OBJECTIVES: This study aimed to design, synthesize, and evaluate twelve selenium-containing carvacrol derivatives as multifunctional anti-Alzheimer agents.

METHODS: The compounds were synthesized via copper-catalyzed azide-alkyne cycloaddition (CuAAC), forming triazole-linked hybrids. Structural characterization was performed using NMR and HRMS. Biological evaluation included in vitro AChE inhibition assays (IC50 determination), antioxidant profiling by cyclic voltammetry, and cytotoxicity screening. Computational studies involved molecular docking (GOLD software), DFT calculations, and ADMET predictions using pkCSM and SwissADME platforms.

RESULTS: Compounds 18e and 18h showed the most potent AChE inhibition (IC50 = 75 and 93 nM, respectively), exhibiting strong interactions with key residues such as Trp286 and Tyr341. Electrochemical assays identified 18l, 18f, and 18c as the most antioxidant derivatives, based on their low oxidation energy. ADMET predictions indicated high intestinal absorption (>95 %), BBB permeability, and no violations of Lipinski's rules. A strong correlation (R[2] = 0.9377) between docking scores and experimental IC50 values supported the reliability of the in silico screening.

CONCLUSION: The synthesized selenium-carvacrol hybrids exhibit a favorable combination of enzyme inhibition, antioxidant capacity, and pharmacokinetic properties. Compounds 18e and 18h demonstrated the most potential and represent valuable leads for future in-depth pharmacological studies and rational optimization in the context of Alzheimer's therapy.},
}

@article {pmid41165744,
year = {2025},
author = {Xiong, S and Cui, M and Liu, H and Wu, L and Xiong, X and Zhang, S and Yang, J and Wang, P},
title = {Rational Design of a Dual-Channel Fluorescent Probe for the Simultaneous Imaging of Brain Amyloid-β Plaques and HClO/ClO[-] in Alzheimer's Disease.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c04718},
pmid = {41165744},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia. The pathological hallmarks of AD are characterized by the presence of amyloid-β (Aβ) plaques and elevated production of hypochlorous acid (HClO/ClO[-]) in the brain. However, there is a lack of effective tools to image the biological functions of Aβ aggregates and HClO/ClO[-] in the AD brain. In this study, we presented the first single-molecule fluorescent probe, CTAD-MB, capable of detecting both Aβ aggregates and HClO/ClO[-]. The design strategy for this probe combines an N,N-dimethyl-phenylcoumarin moiety, which has high affinity for Aβ aggregates, with a methylene blue derivative that specifically responds to hypochlorite. This bifunctional fluorescent probe provided distinct fluorescent signals for Aβ aggregates and HClO/ClO[-]. CTAD-MB demonstrated completely independent spectral responses to Aβ and HClO/ClO[-], offering high selectivity, sensitivity, and rapid response. The probe was successfully employed in imaging the HClO/ClO[-] stimulated by Aβ aggregates in PC12 cells. Also, it was effectively applied for dual-channel detection of Aβ and HClO/ClO[-] in the live AD mouse, which could be used to distinguish from the brain inflammation mouse. This insight not only advances our understanding of AD but also provides new avenues for its diagnosis and treatment.},
}

@article {pmid41165739,
year = {2025},
author = {Dalal, N and Jaiswal, J and Kushwaha, M and Verma, H and Rana, P and Gupta, S and Panwar, R and Janmeda, P and Jain, P and Singh, AK and Mohan, A and Kumar, A},
title = {Implications of Gut Microbiota-Derived Metabolites in Neurological Disorders.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00414},
pmid = {41165739},
issn = {1948-7193},
abstract = {Neurological disorders (NDs) represent a significant global health challenges, with neurodegeneration being a common pathological feature. Recent investigations indicate the involvement of gut microbiota-derived metabolites in these disorders, such as neuroinflammation, oxidative stress, and cognitive decline. The gut-brain axis, a communication network between the gut and the central nervous system (CNS), is influenced by microbial metabolites, which can cross the blood-brain barrier and impact brain function. Key metabolites such as trimethylamine N-oxide (TMAO), para-cresol sulfate (pCS), 4-ethylphenyl sulfate (4-EPS), and indoxyl sulfate (IS) have been linked with the progression of neurological disorders. TMAO disrupts blood-brain barrier integrity, promotes oxidative stress, and activates microglial cells, which lead to the apoptosis of neurons, resulting in neuroinflammation. This could also result in psychiatric changes and behavioral disorders. pCS produced from gut bacteria metabolizing dietary proteins is correlated with amplified oxidative stress, neuroinflammation, and cognitive impairments in disorders like Parkinson's disease and Alzheimer's disease. Similarly, elevated 4-EPS levels are linked to autism spectrum disorder, contributing to anxiety-like behavior and blood-brain barrier disruption. Understanding the mechanisms by which gut-derived metabolites affect neurological health could lead to novel therapeutic strategies that can target gut microbiota for the medication and treatment of neurological disorders. Dietary precursors and gut microbiota metabolites, modulated by probiotics, prebiotics, postbiotics, and synbiotics, play a critical role in maintaining microbiota homeostasis and influencing neurological health, needing sophisticated biosensors to enable real-time monitoring and early intervention in disorders linked to gut metabolite imbalances.},
}

@article {pmid41165158,
year = {2025},
author = {Hao, J and Wan, Q and Chen, C},
title = {Atractylenolide III Promotes Astrocyte Aβ Clearance by Up-regulating AQP4 to Improve Alzheimer's Disease.},
journal = {Folia biologica},
volume = {71},
number = {3},
pages = {140-148},
doi = {10.14712/fb2025071030140},
pmid = {41165158},
issn = {0015-5500},
support = {D202303076913//Health Commission of Hunan Province/ ; D202304017019//Health Commission of Hunan Province/ ; },
mesh = {*Astrocytes/metabolism/drug effects ; Animals ; *Aquaporin 4/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Sesquiterpenes/pharmacology/therapeutic use/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Lactones/pharmacology/therapeutic use/chemistry ; Mice ; *Up-Regulation/drug effects ; Molecular Docking Simulation ; Male ; Disease Models, Animal ; Cell Survival/drug effects ; Mice, Inbred C57BL ; Peptide Fragments/metabolism ; },
abstract = {Astrocytes actively phagocytose amyloid beta (Aβ), enhancing cerebral clearance and positioning themselves as viable therapeutic targets for Alz-heimer's disease (AD). Atractylenolide III (ATL-III), the primary bioactive compound in the traditional Chinese herb Baizhu, demonstrates established neuroprotective properties. However, the research on its effects on astrocytes has not yet been elaborated. To induce an astrocyte-based AD model, Aβ1-42 was utilized. Cell viability assays were conducted to screen for the optimal concentration of ATL-III treatment. Molecular docking was performed to investigate the binding between ATL-III and aquaporin 4 (AQP4). Additionally, an Aβ1-42-induced AD mouse model was adopted. In this study, ATL-III effectively reduced the accumulation level of Aβ1-42 in the cell supernatant, and at the same time, significantly enhanced the internalization of Aβ by astrocytes. Of interest, the study reveals that ATL-III not only has the property of binding to AQP4 but also up-regulates the expression level of this protein. Mechanistic probes suggest that the role of ATL-III in promoting Aβ clearance by astrocytes may be partially dependent on its regulation of AQP4 expression. Animal behavioural experiments confirmed that the compound ameliorated Aβ1-42-induced cognitive dysfunction, and pathological analyses revealed significantly elevated AQP4 expression in the hippocampus. The combined findings suggest that ATL-III may play a role in ameliorating the pathological process of AD by enhancing the efficiency of astrocyte-mediated Aβ clearance through the up-regulation of AQP4 expression.},
}

*Astrocytes/metabolism/drug effects
Animals
*Aquaporin 4/metabolism/genetics
*Amyloid beta-Peptides/metabolism
*Sesquiterpenes/pharmacology/therapeutic use/chemistry
*Alzheimer Disease/drug therapy/metabolism
*Lactones/pharmacology/therapeutic use/chemistry
Mice
*Up-Regulation/drug effects
Molecular Docking Simulation
Male
Disease Models, Animal
Cell Survival/drug effects
Mice, Inbred C57BL
Peptide Fragments/metabolism

@article {pmid41165142,
year = {2025},
author = {Chen, YN and Xiong, ZE and Wen, X and He, SJ and Zhang, XL and Zhang, R and Wang, T and Zou, J},
title = {Anthocyanins in the treatment of Alzheimer's disease: a systematic review and meta-analysis of animal studies.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/1028415X.2025.2578641},
pmid = {41165142},
issn = {1476-8305},
abstract = {BACKGROUND: To comprehensively evaluate the therapeutic potential of anthocyanins in animal models of Alzheimer's disease (AD).

METHODS: The PubMed, Web of Science, and Embase databases were searched for preclinical animal studies investigating anthocyanin intervention in AD models up to June 2025. Studies reporting outcomes related to cognitive behavior, neuropathological changes such as amyloid-β (Aβ) deposition, or molecular mechanisms including oxidative stress and inflammatory markers, were included in the analysis. Data analysis was performed using RevMan 5.4 software. The SYRCLE tool was used to assess the risk of bia.

RESULTS: Anthocyanin intervention significantly improved cognitive function in animal models of AD. Meta-analysis revealed that in the Morris water maze test, the anthocyanin treatment group exhibited a significantly higher number of crossings in the target quadrant compared to the control group (SMD = 1.83, 95% CI: 1.48 -2.18, p < 0.00001). Regarding pathological indicators, anthocyanin administration was associated with a significant reduction in Aβ protein deposition (SMD = -5.39, 95% CI: - 6.89 to - 3.88, p < 0.00001). Furthermore, anthocyanin effectively alleviated oxidative stress, as evidenced by a significant decrease in malondialdehyde (MDA) levels (SMD = -4.19, 95% CI: - 6.76 to - 1.63, p = 0.001). In terms of neuroinflammatory markers, anthocyanin treatment significantly reduced the expression levels of tumor necrosis factor-alpha (TNF-α) (SMD = -3.30, 95% CI: - 4.91 to - 1.68, p < 0.0001) and interleukin-1 beta (IL-1β) (SMD = -2.23, 95% CI: - 3.12 to - 1.34, p < 0.00001).

CONCLUSION: This systematic review and meta-analysis suggest that anthocyanins could improve cognitive function and mitigate neuropathology in animal models of AD.},
}

@article {pmid41164883,
year = {2025},
author = {André, C and Stankeviciute, L and Michaelian, JC and Antonsdottir, IM and Benca, RM and Coulthard, EJ and D'Rozario, AL and Dijk, DJ and Gimenez, S and Gorgoni, M and Leng, Y and Lucey, BP and Pase, MP and Rainey-Smith, SR and Rosenzweig, I and Spira, AP and Winer, JR and Rauchs, G and Naismith, SL and , },
title = {International recommendations for sleep and circadian research in aging and Alzheimer's disease: A Delphi consensus study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70742},
doi = {10.1002/alz.70742},
pmid = {41164883},
issn = {1552-5279},
support = {//Alzheimer's Association International Society/ ; //Advance Alzheimer's Research and Treatment/ ; //Sleep and Circadian Rhythms/ ; //PIA membership, ISTAART,/ ; /ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology ; Delphi Technique ; *Aging/physiology ; *Circadian Rhythm/physiology ; Consensus ; *Sleep/physiology ; *Sleep Wake Disorders ; *Biomedical Research ; },
abstract = {INTRODUCTION: Research in the field of sleep, aging, and dementia is rapidly growing. Consensus guidance is needed to facilitate high-quality research, comparability, and consistency.

METHODS: A modified Delphi consensus study was conducted by the Sleep and Circadian Rhythms Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment (ISTAART) and an international panel of experts to establish recommendations for future research.

RESULTS: After two voting rounds, the group (1) determined by consensus the most relevant sleep and circadian features to assess in the context of aging and dementia research, (2) established recommendations on data acquisition and report for future studies, and (3) identified high-priority future directions.

DISCUSSION: This expert consensus study provides guidance to develop high-quality sleep and circadian research in the context of aging and dementia. Similar recommendations will need to be established for clinical practice.

HIGHLIGHTS: We report the results of an international expert consensus study. Sleep and circadian rhythms features relevant to aging and dementia were identified. Recommendations on data acquisition and reporting were established. High-priority future research directions were identified.},
}

Humans
*Alzheimer Disease/physiopathology
Delphi Technique
*Aging/physiology
*Circadian Rhythm/physiology
Consensus
*Sleep/physiology
*Sleep Wake Disorders
*Biomedical Research

@article {pmid41164820,
year = {2025},
author = {Summanwar, D and Owora, AH and Ben Miled, Z and Dexter, PR and Kulshreshtha, A and Strunk, S and Jiang, B and Coppedge, K and Disla, S and Galvin, JE and Boustani, M and Fowler, NR},
title = {Prevalence of Multiple Chronic Conditions in Older Adults with Undiagnosed Mild Cognitive Impairment and Alzheimer's Disease and Related Dementias in Primary Care.},
journal = {Clinical interventions in aging},
volume = {20},
number = {},
pages = {1799-1809},
pmid = {41164820},
issn = {1178-1998},
mesh = {Humans ; Aged ; *Cognitive Dysfunction/epidemiology/diagnosis ; Male ; Female ; Cross-Sectional Studies ; *Primary Health Care/statistics & numerical data ; *Alzheimer Disease/epidemiology/diagnosis ; Aged, 80 and over ; Prevalence ; *Multiple Chronic Conditions/epidemiology ; Indiana/epidemiology ; Florida/epidemiology ; *Dementia/epidemiology/diagnosis ; },
abstract = {BACKGROUND: Most adults aged ≥65 years live with multiple chronic conditions (MCC), and nearly one in four have recognized or unrecognized Alzheimer's disease and related dementias (ADRD), including an estimated 7.2 million Americans. Together, MCC and ADRD increase treatment complexity, medication burden, and the risk of adverse outcomes. Among patients who meet clinical criteria for mild cognitive impairment (MCI) or ADRD but lack a formal diagnosis, MCC burden remains unclear. This study examined the association between MCC burden and undiagnosed MCI and ADRD in a diverse cohort of older adults in primary care.

METHODS: We conducted a cross-sectional analysis of 324 adults aged ≥65 from primary care clinics in Indiana and South Florida (2021-2023), as part of a larger ADRD detection study. Patients without documented MCI or ADRD completed standardized cognitive assessments. Cognitive status (normal, MCI, ADRD) was determined by interdisciplinary consensus. Chronic conditions and medications were extracted from electronic health records. Multinomial logistic regression was used to examine the association between MCC profiles and cognitive status.

RESULTS: Among 324 older adults, 51.9% were determined to have MCI and 8% ADRD. Patients with MCI and ADRD had more chronic conditions (mean = 5-6) and medications (mean = 4-5) than those with normal cognition (p < 0.001). Anticholinergic use was more common in the MCI (23.8%) and ADRD (23.1%) groups than in those with normal cognition (10.8%). In adjusted models, MCI and ADRD were associated with higher odds of having more chronic conditions. Cerebrovascular disease was associated with both MCI and ADRD; diabetes, sleep apnea, and insomnia with MCI; and ischemic heart disease and insomnia with ADRD.

CONCLUSION: Older adults with unrecognized MCI and ADRD experience substantial MCC and medication burden. These findings highlight the need for targeted primary care interventions that integrate cognitive screening, support MCC management, optimize self-management capacity, and promote safer prescribing.},
}

Humans
Aged
*Cognitive Dysfunction/epidemiology/diagnosis
Male
Female
Cross-Sectional Studies
*Primary Health Care/statistics & numerical data
*Alzheimer Disease/epidemiology/diagnosis
Aged, 80 and over
Prevalence
*Multiple Chronic Conditions/epidemiology
Indiana/epidemiology
Florida/epidemiology
*Dementia/epidemiology/diagnosis

@article {pmid41164318,
year = {2025},
author = {Yaghmaei, E and Dillard, A and Rezaei, M and Rezaie, A and Pierce, A and Lu, H and Adams, E and Todorov, N and Ehwerhemuepha, L and Zheng, J and Sajjadi, SA and Bazargan, M and Rakovski, C},
title = {Comprehensive descriptive analysis of large Alzheimer's disease patient cohorts.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251385560},
pmid = {41164318},
issn = {2542-4823},
abstract = {BACKGROUND: Precise estimates of the prevalence of Alzheimer's disease (AD), the distribution of demographic characteristics, comorbidities, treatment plans, insurance types, cost of treatment and survival probabilities at various time points are crucially important to advancing our understanding and for improving future AD research studies.

OBJECTIVE: We analyzed two of the largest and high-quality medical databases, Oracle EHR Real-World Data and IQVIA. The results provide the most complete description of the AD patients in the US.

METHODS: We present high-accuracy summary statistics of many important variables related to AD patients. Proportions, means and 95% confidence intervals were provided for all levels of the categorical and quantitative variables.

RESULTS: We report high accuracy estimates of the overall survival probabilities for the first five years after initial diagnosis, drug treatments and patterns of use, demographics, insurance types, hospitalization duration, number of hospital visits, and a detailed list of comorbidities. We also report estimates of the annual total average cost of treatment per patient as well as itemized allocations for drugs, hospitalizations, surgery, and management costs.

CONCLUSIONS: We present the most complete, detailed and high-accuracy descriptive analysis of AD patients to date.},
}

@article {pmid41164084,
year = {2025},
author = {Zhu, L and Cai, M and Lu, Z and Wang, Q and Zhai, T and Hu, J},
title = {The impact of high-intensity interval training on cerebrovascular function in the APP/PS1 mice.},
journal = {Frontiers in aging},
volume = {6},
number = {},
pages = {1647628},
pmid = {41164084},
issn = {2673-6217},
abstract = {ABSTRACT: Alzheimer's disease (AD), the most commonly diagnosed form of senile dementia worldwide, is closely associated with aging and distinct neuropathological features. Recent studies highlight that up to 90% of individuals, either preclinical or clinical, diagnosed with vascular pathology in the context of AD exhibit thickening and hyalinization of the media in small and medium-sized cerebral vessels. Exercise has emerged as a potential, non-pharmaceutical, and cost-effective intervention for the prevention and treatment of AD. However, there is limited research exploring the effects of high-intensity interval training (HIIT) on cerebrovascular function in AD.

METHODS: Four-month-old female C57BL/6 J mice and APP/PS1 transgenic mice were initially acclimated to a standard diet for 1 week. The two groups were then divided into sedentary and exercise cohorts, with the exercise group engaging in a 6-week HIIT regimen. Post-intervention, hippocampal specimens were collected for analysis. Aβ and Tau protein levels were measured to assess AD pathology, while cognitive function was evaluated using the eight-arm radial maze and BDNF mRNA expression. Additionally, markers of cerebrovascular function-including VEGF, EPO, eNOS, GPR68, and ET-1-were examined, and HIF-1α was utilized to assess the hippocampal response to AD pathology.

RESULTS: HIIT significantly reduced reference memory errors (p = 0.025) and markedly upregulated Bdnf mRNA expression (p < 0.001) specifically in APP/PS1 mice. Furthermore, HIIT significantly decreased protein levels of AD pathological markers p-TAU (p = 0.001) and APP (p = 0.002) in APP/PS1 mice. HIIT significantly increased the mRNA (p < 0.001) and protein (p = 0.003) levels of EPO and Vegfa mRNA (p < 0.001) levels to stimulate pro-angiogenic signal in APP/PS1 mice. HIIT also significantly increased both the mRNA and proteins levels of eNOS expression (p < 0.001) while decreasing the mRNA and proteins levels of ET-1 (p < 0.001) and GPR68 (p < 0.001) to enhance vasodilation in APP/PS1 mice. Finally, HIIT significantly increased HIF-1α expression at both protein and mRNA levels (p < 0.001), independent of genotype.

CONCLUSION: HIIT ameliorates cognitive function and reduces hallmark AD pathology. This positive effect is potentially mediated through cerebral microangiogenesis, cerebrovascular function regulation, and hypoxic metabolism. HIIT represents a promising non-pharmacological strategy for targeting multiple aspects of AD pathophysiology.},
}

@article {pmid41163934,
year = {2025},
author = {Jafari, M and Alipour, M and Zamani, S and Mohtasham Amiri, A and Pourabbas, P and Hasannejad-Bibalan, M},
title = {Probiotics as a Complementary Medicine in Neurologic Disorders.},
journal = {Health science reports},
volume = {8},
number = {11},
pages = {e71422},
pmid = {41163934},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: Today, neurological and neuropsychiatric disorders, including depression, anxiety, Parkinson's disease (PD), Alzheimer's disease (AS), autism spectrum disorder (ASD), and multiple sclerosis (MS), contribute significantly to global disability and healthcare burden. Most current treatment options only provide symptomatic relief and are limited by challenges such as drug resistance, systemic side effects, and poor blood-brain barrier permeability. The growing interest in the gut-brain axis has encouraged exploration of the gut microbiota as a potential therapeutic target. Probiotics-live microorganisms that may confer health benefits to the host-have been proposed to modulate the gut-brain axis through immune, metabolic, and neurochemical pathways.

METHODS: In this narrative review, a targeted search was performed across multiple databases to identify relevant articles, from which the key relationships and strategies were extracted. Then, we represented the findings to provide a comprehensive overview of the topic and highlight emerging trends and gaps in the literature.

RESULTS: Emerging preclinical and clinical studies suggest that specific probiotic strains can improve neurological symptoms by reducing neuroinflammation, supporting gut barrier integrity, and influencing neurotransmitter production. However, findings remain heterogeneous due to strain specificity, individual microbiome diversity, and methodological differences across studies. Preclinical and clinical studies suggest that specific probiotic strains can improve neurological symptoms by reducing neuroinflammation, enhancing gut barrier integrity, and influencing neurotransmitter production. Evidence supports their potential as adjunctive treatments for major neurological and neuropsychiatric disorders, including depression, anxiety, ASD, PD, AD, and MS, particularly in patients with gut dysbiosis or gastrointestinal comorbidities. However, findings remain heterogeneous due to strain specificity, individual microbiome variability, and methodological differences across studies.

CONCLUSION: This brief review summarizes the current evidence on the use of probiotics in neurological disorders, discusses potential mechanisms of action, and highlights safety considerations and limitations. Future directions include personalized probiotic therapies, large-scale randomized controlled trials, and integration with conventional neurological therapies. Overall, probiotics could be a low-risk, complementary option in the evolving field of neurotherapy, but more rigorous evidence is needed before definitive clinical recommendations can be made.},
}

@article {pmid41163844,
year = {2025},
author = {Kurban, B and Sağlık Özkan, BN and Osmaniye, D and Levent, S and Özkay, Y and Kaplancıklı, ZA},
title = {Structure-based design, synthesis, and biological activity evaluation of chalcone-piperazine derivatives as dual AChE and MAO B inhibitors.},
journal = {RSC advances},
volume = {15},
number = {48},
pages = {40897-40911},
pmid = {41163844},
issn = {2046-2069},
abstract = {The development of pharmaceutical compounds for the treatment of Alzheimer's Disease (AD) and other neurodegenerative diseases is crucial, as the pathophysiology of AD remains incompletely understood and effective treatments are still lacking. In this study, a series of novel compounds based on Donepezil, incorporating piperazine and chalcone structures, were designed, synthesized, and characterized. The structures of the compounds were confirmed using IR, [1]H-NMR, [13]C-NMR, and HRMS techniques. Biological activities of the compounds were evaluated against cholinesterase enzymes and monoamine oxidase enzymes. The most potent derivative against acetylcholinesterase (AChE) was compound 4g, with an IC50 value of 0.027 ± 0.001 μM, and the most potent against monoamine oxidase B (MAO B) was also 4g, with an IC50 value of 0.114 ± 0.003 μM. In silico studies further elucidated the interaction of compound 4g with AChE. Molecular docking revealed key interactions between 4g and amino acids in the AChE active site. A 100 ns molecular dynamics simulation confirmed the stability of the 4g-AChE complex.},
}

@article {pmid41163274,
year = {2025},
author = {Sanghvi, G and Deepak, A and R, R and Ariffin, IA and Kashyap, A and Chahar, M and Nanda, A and Ray, S and Joshi, KK},
title = {Chondroitinase ABC in Neural Regeneration: Advances in CNS and Peripheral Nerve Repair.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128392818251012115510},
pmid = {41163274},
issn = {1873-4286},
abstract = {Chondroitinase ABC (ChABC) is a bacterial enzyme that can potentially address the inhibitory effects of Chondroitin Sulfate Proteoglycans (CSPGs) in various neurological disorders and injuries. CSPGs are key components of the extracellular matrix that, when accumulated after Central Nervous System (CNS) injury or neurodegenerative diseases, inhibit axonal growth and tissue repair. This review explores the therapeutic potential of ChABC in Spinal Cord Injury (SCI), Traumatic Brain Injury (TBI), stroke, Parkinson's Disease (PD), Alzheimer's Disease (AD), and peripheral nerve regeneration. ChABC's mechanism of action involves the degradation of CSPGs, promoting neural plasticity, axonal regeneration, and functional recovery in SCI and other CNS injuries. In stroke and TBI, ChABC treatment has been shown to enhance neurogenesis, reduce glial scar formation, and support neuronal survival. In neurodegenerative conditions like PD and AD, ChABC's ability to modify the inhibitory extracellular environment offers novel strategies for promoting neuronal repair and cognitive function. Additionally, ChABC has been explored in cancer therapy, where its ability to degrade the tumor extracellular matrix facilitates improved drug delivery and tumor infiltration. While ChABC holds promise, challenges remain in its clinical application, particularly regarding stability, targeted delivery, and long-term effects. This review discusses the mechanism of action of ChABC and various delivery strategies, including viral vectors and localized infusion, and emphasizes the need for further research to optimize ChABC's potential. The future of ChABC in regenerative medicine depends on overcoming these barriers, improving delivery methods, and exploring synergistic treatments for enhanced recovery outcomes.},
}

@article {pmid41163120,
year = {2025},
author = {Juan, Y and Wei, T and Weiwei, Z and Dongdong, S and Mengjie, Z and Xuefeng, W and Xianglong, L and Yuelong, S and Jinhua, Z and Xiumei, L},
title = {Regulation on microbial composition,serotonergic synapse, and apoptotic signaling pathway by extracts fromSonchus brachyotus DC. (SBE) to improve ethanol-induced acute oxidative stress in mice.},
journal = {Microbiome},
volume = {13},
number = {1},
pages = {221},
pmid = {41163120},
issn = {2049-2618},
support = {CAAS-IFR-ZDRW202406//The Agricultural Science and Technology Innovation Program/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; Mice ; *Gastrointestinal Microbiome/drug effects ; *Apoptosis/drug effects ; Signal Transduction/drug effects ; *Plant Extracts/pharmacology ; Ethanol/toxicity/adverse effects ; Male ; *Synapses/drug effects/metabolism ; Bacteria/classification/genetics/drug effects/isolation & purification ; Antioxidants/pharmacology ; *Sonchus/chemistry ; RNA, Ribosomal, 16S/genetics ; },
abstract = {BACKGROUND: Oxidative stress has been firmly established as a pivotal contributor to the pathogenesis of inflammatory bowel disease, diabetes mellitus, Alzheimer's disease, and other multifactorial disorders. Our previous findings have demonstrated the extracts from Sonchus brachyotus DC. (SBE) mitigates intestinal oxidative stress through interactions between the oxidative stress biomarkers and gut microbiota. However, we did not focus on the mechanism by which SBE exerts antioxidant stress effects through regulating metabolites and genes, nor the correlation between the two and gut microbiota. Therefore, this study aimed to elucidate the underlying mechanism by which SBE mitigates oxidative stress through the gut microbiota, metabolites, and genes.

RESULTS: Supplementation with SBE exerts a promising regulatory effect on oxidative stress by modulating key oxidative stress biomarkers (e.g., GSH, SOD, etc.) in serum, intestine, liver, and brain tissues in ethanol-model mice. And the SBE treatment exhibited a notable reparative effect on intestine, liver, and brain tissue damage. Concomitantly, 16S rRNA and ITS sequencing revealed significant alterations in the composition of intestinal bacteria and fungi in SBE-treated mice, suggesting the restoration of gut microbiota homeostasis. Spearman correlation analysis further indicated significant associations (p < 0.05) between gut microbes, particularly fungal genera, and oxidative stress biomarkers. Notably, the abundance of specific fungal genera (Alternaria and Pichia), the levels of 14,15-DiHETrE, 5-Hydroxyindole-3-acetic acid, and prostaglandin C2 key metabolites of the serotonergic synapse pathway, and the expression of Fas and Tnfsf10 key genes of apoptosis signaling pathway were significantly correlated (p < 0.05) based on the constructed correlation network. This mechanism likely triggers coordinated changes in metabolites and gene expression associated with the serotonergic synapse and apoptosis signaling pathways, ultimately leading to multi-targeted amelioration of oxidative stress. Molecular docking further revealed that trigonelline, mesaconic acid, and salicylic acid, bioactive components of SBE, may exhibit considerable binding affinity with Fas and Tnfsf10, providing a potential structural basis for SBE's regulatory effects on oxidative stress via modulation of the apoptotic signaling.

CONCLUSIONS: The antioxidant effects of SBE likely involve multi-pathway and multi-target mechanisms, consistent with the combinatorial properties of its herbs constituents. These findings lays a foundation for subsequent research. Video Abstract.},
}

Animals
*Oxidative Stress/drug effects
Mice
*Gastrointestinal Microbiome/drug effects
*Apoptosis/drug effects
Signal Transduction/drug effects
*Plant Extracts/pharmacology
Ethanol/toxicity/adverse effects
Male
*Synapses/drug effects/metabolism
Bacteria/classification/genetics/drug effects/isolation & purification
Antioxidants/pharmacology
*Sonchus/chemistry
RNA, Ribosomal, 16S/genetics

@article {pmid41162940,
year = {2025},
author = {Arif, M and Musleh, S and Alam, T},
title = {DeepB[3]Pred: blood-brain barrier peptide predictor using stacked BiGRU model with novel features.},
journal = {BMC biology},
volume = {23},
number = {1},
pages = {325},
pmid = {41162940},
issn = {1741-7007},
mesh = {*Blood-Brain Barrier/metabolism ; *Deep Learning ; *Computational Biology/methods ; *Cell-Penetrating Peptides/chemistry ; *Peptides/chemistry ; },
abstract = {BACKGROUND: The blood-brain barrier (B[3]) acts as a membrane that is a major concern in treating central nervous system (CNS) disorders. The B[3] penetrating peptides (B[3]PPs) play a significant role in delivering therapeutic drugs to a wide range of disorder diseases such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Therefore, the correct identification of drug agents is important for the disease treatment. Generally, the computational methods are more cost effective and faster than conventional wet-lab methods in predicting B[3]PPs. Consequently, we have developed a novel deep learning-based predictor called DeepB[3]Pred that accurately predicts the B[3]PPs and non-B[3]PPs from sequence data.

RESULTS: In the proposed method, we used three types of novel features namely Pseduo residue energy content matric (PseRECM), graphical and statistical-based feature engineering (GSFE), and composition-transition and distribution (CTD)-based features. These features capture the energy-, graphical-, and compositional-based properties of from the primary peptide sequences. The data skewness is recognized as an inevitable issue that was tackled by employing a random under sampling technique. The extracted data were fed into various deep learning, i.e., stacked bidirectional gated recurrent unit (BiGRU), Deep Forest, and machine learning models, i.e., CatBoost, Support Vector Machine.   BiGRU-based DeepB[3]Pred model attained better results than the other state-of-the-art B[3]PPs predictors. The prediction efficacy of the proposed model on fivefold cross-validation in terms of accuracy is 0.945, MCC of 0.877, and area under the curve (AUC) of 0.965. The generalization performance on the unseen data is reported as 0.869 for accuracy, 0.635 for MCC, and 0.933 for AUC.

CONCLUSION: We believe our research will accelerate the peptide-based drug discovery for neurological diseases in particular.},
}

*Blood-Brain Barrier/metabolism
*Deep Learning
*Computational Biology/methods
*Cell-Penetrating Peptides/chemistry
*Peptides/chemistry

@article {pmid41161455,
year = {2025},
author = {Ishaq, K and Arputharaj, E and Khan, MB and Dahms, HU and Delattre, C and Chao, YY and Huang, YL},
title = {Turning an adversary into an ally: Self-assembled amyloid-like fibril aerogel packed 3D-printed microfluidic sample pre-treatment device for elemental analysis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148590},
doi = {10.1016/j.ijbiomac.2025.148590},
pmid = {41161455},
issn = {1879-0003},
abstract = {In this study, we transformed well-known disease-causing amyloid fibrils into a functional ally. Instead of using Alzheimer's disease associated amyloid-beta fibrils we employed synthetic lysozyme derived amyloid-like fibrillar aggregates. We developed a simple and effective method for enriching and detecting various toxic elements in complex serum samples. This method employs a reusable 3D-printed microfluidic sample pre-treatment device, packed with a bio-based aerogel elemental ion extractant composed of self-assembled amyloid-like lysozyme fibrillar aggregates (AF), graphitic carbon nitride nanosheets (g-C3N4 NSs), and polyethyleneimine (PEI). The developed setup is integrated with inductively coupled plasma mass spectrometry (ICP-MS), enabling accurate elemental analysis without interference from the sample matrix. The synthesized elemental ion extractant aerogel is rich in diverse functional groups, significantly enhances the element extraction efficiency compared to conventional toxic element sorbents lacking structured amyloid-like networks. The established method yielded significant detection limits ranging from 1 to 100 μg L[-1] for Ag[+], Cr[3+] and Se IV over other elements with relative standard deviations (RSDs) between 2.1 and 4.6 %. Specifically, the approach achieved a limit of detection (LOD) of 0.2 μg L[-1] for Cr, 0.4 μg L[-1] for Se, and 1.1 μg L[-1] for Ag. High recovery rates ranging from 85 to 102 % were achieved in spiked complex serum matrices. Moreover, the proposed multifunctional 3D-printed microfluidic approach significantly enhanced the selective extraction and detection of toxic elements in complex serum samples, demonstrating robust performance over seven adsorption-desorption cycles and representing a sustainable and significant analytical advancement.},
}

@article {pmid41161293,
year = {2025},
author = {Sahoo, SS and Paidesetty, SK and Sahu, PK and Pattanaik, S and Dandela, R},
title = {Therapeutic innovation through drug repurposing: A multidimensional approach toward treating Parkinson's disease.},
journal = {Bioorganic chemistry},
volume = {166},
number = {},
pages = {109129},
doi = {10.1016/j.bioorg.2025.109129},
pmid = {41161293},
issn = {1090-2120},
abstract = {Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease, primarily affecting the aging population. Despite the introduction of levodopa in the 1960s and significant progress in managing PD symptoms, no treatment has yet demonstrated neuroprotective efficacy. The complexity and multifactorial nature of PD continue to present substantial therapeutic challenges, prompting researchers to explore alternative approaches such as drug repurposing. This strategy offers a time- and cost-efficient route to drug development. Recent efforts have focused on repurposing agents originally developed for metabolic and other non-neurological disorders. Ongoing research is actively investigating several repurposed drugs originally intended for different conditions, including anti-hypertensives (isradipine, dexmedetomidine), anti-asthmatics (montelukast), phosphodiesterase5 inhibitors (sildenafil), antimicrobials (rifaximin), and various CNS-active agents (aripiprazole, escitalopram, paroxetine, venlafaxine, duloxetine, caffeine). While drug repurposing holds considerable promise, comprehensive preclinical and clinical studies are essential to validate these candidates for PD-specific therapeutic applications. This review aims to provide an in-depth overview of PD, encompassing its pathological and molecular characteristics, and to critically evaluate the current landscape of drug repurposing strategies to develop effective therapies for PD.},
}

@article {pmid41160917,
year = {2025},
author = {Rößler, H and Hamzehpour, L and Grimm, O},
title = {Transdiagnostic neuroanatomical risk in schizophrenia: integrating regional vulnerability indices with anthropometric and fitness-based markers of cardiometabolic health.},
journal = {NeuroImage. Clinical},
volume = {48},
number = {},
pages = {103897},
doi = {10.1016/j.nicl.2025.103897},
pmid = {41160917},
issn = {2213-1582},
abstract = {Schizophrenia is a multisystem disorder affecting both brain and body, with patients exhibiting substantial somatic comorbidities including obesity, reduced physical fitness, and elevated cardiometabolic risk. While neuroimaging-derived Regional Vulnerability Indices (RVIs) have quantified brain structural deviations from disorder-specific patterns, their relationship to physical health in schizophrenia remains largely unexplored. In this study, we combined RVIs with detailed anthropometric and fitness assessments in 42 schizophrenia patients and 43 matched healthy controls. Participants underwent MRI-based cortical thickness analyses to derive RVIs for nine psychiatric, neurological, and metabolic disorders, alongside measurements of body composition, cardiorespiratory fitness, handgrip strength, and jump performance. Patients exhibited significantly higher RVIs for schizophrenia (Cohen's D = -1.1), bipolar disorder (Cohen's D = -0.9), Alzheimer's (Cohen's D = -0.6) and Parkinson's disease (Cohen's D = -0.7), and type 2 diabetes (Cohen's D = -0.9). These overlapping neuroanatomical vulnerabilities across psychiatric, neurodegenerative, and metabolic conditions might reflect shared underlying genetic and physiological mechanisms. Principal component analysis revealed three latent dimensions: (1) general risk factors, (2) physical fitness deficits, and (3) psychosis-spectrum vulnerability, with the latter two showing significant differences between groups. These findings highlight that metabolic impairment and reduced physical fitness in schizophrenia are not merely secondary phenomena but constitute distinct dimensions of systemic vulnerability. Overall, our results support a brain-body conceptualization of schizophrenia, suggesting that RVIs may serve as biomarkers to guide precision medicine interventions integrating neuroprotective strategies with lifestyle management. Future research should incorporate longitudinal and multimodal assessments to clarify causal relationships and optimize individualized treatment approaches.},
}

@article {pmid41160464,
year = {2025},
author = {Kim, M and Kwon, H and Sohn, S and Lee, WJ and Cho, K and Kim, GW},
title = {Alzheimer's disease diagnosis and treatment: From pathophysiological insights to therapeutic advances in the era of precision neurology (2025 review).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251391820},
doi = {10.1177/13872877251391820},
pmid = {41160464},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, functional impairment, and ultimately, loss of independence. Traditional models centered on amyloid-β and tau pathology have expanded to encompass interconnected processes such as neuroinflammation, synaptic dysfunction, and gut-brain axis disruption, underscoring the multifactorial nature of the disease. In this review, we delivered that advances in diagnosis now integrate fluid biomarkers within the A/T/N/X framework, high-resolution neuroimaging, and artificial intelligence, enabling earlier and more precise disease characterization. On the therapeutic front, the approval of anti-amyloid monoclonal antibodies marks a paradigm shift toward disease-modifying approaches, yet challenges remain regarding efficacy, safety, and accessibility. Complementary strategies, including cognitive interventions and innovative drug delivery systems, highlight the need for multidimensional care that extends beyond pharmacology to improve patient quality of life. Furthermore, emerging avenues such as stem cell therapy, multitarget drug development, and precision medicine approaches illustrate a field in transition-shifting from symptomatic management toward personalized strategies aimed at altering the course of AD.},
}

@article {pmid41160460,
year = {2025},
author = {Cury, RM and da Silva, T and Cezar-Dos-Santos, F and Fakih, YRC and Narvaez, KAR and Gouvea, MC and Espínola, C and Ferreira, CF and de Castro, WAC and Pamplona, FA and Silva, EGD and Bicca, MA and Nascimento, FP},
title = {A randomized clinical trial of low-dose cannabis extract in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389608},
doi = {10.1177/13872877251389608},
pmid = {41160460},
issn = {1875-8908},
abstract = {BackgroundPreclinical and clinical evidence suggest that low-dose cannabinoids could ameliorate Alzheimer's disease (AD) signs and symptoms. We designed this trial to evaluate the safety and efficacy of low-dose THC-CBD balanced cannabinoid extract in the treatment of patients with AD-associated dementia.ObjectiveThe objective of this phase 2 trial was to evaluate the safety and efficacy of a balanced THC-CBD cannabinoid extract for symptomatic patients with AD.MethodsA Phase 2, randomized, double-blind, placebo-controlled, clinical trial including patients between 60 and 80 years-old diagnosed with AD-associated dementia. For 26 weeks, participants orally received either placebo or THC-CBD extract (0.350 mg/THC and 0.245 mg/CBD), daily.ResultsAt week 26, Mini-Mental State Exam total score was significantly higher in cannabis- when compared to placebo-treated patients, which was assessed using the mixed model analysis. No significant difference was detected between placebo and cannabis groups in terms of secondary outcomes and adverse events incidence.ConclusionsTo this date, this is the longest clinical trial evaluating cannabinoids effects on AD patients. We initially demonstrate that low-dose THC-CBD potentially can be an effective and safe therapeutic option for AD-related dementia. Nonetheless, larger and longer trials are necessary to confirm this finding and establish cannabinoid administration as therapy for AD dementia.Trial RegistrationThe Brazilian Registry of Clinical Trials (ReBEC) registration #U1111-1258-2058 - REBEC (ensaiosclinicos.gov.br).},
}

@article {pmid41160443,
year = {2025},
author = {Lim, MJ and Cheung, CY and Chong, JR and Chua, J and Hilal, S and Lai, MK and Maier, AB and Schmetterer, L and Tan, BY and Venketasubramanian, N and Wong, TY and Xu, X and Yeo, BT and Zhou, JH and Chen, CL},
title = {HARMONISATION - A multimodal prospective study of vascular cognitive impairment in multi-ethnic Asians: Cohort profile, progress, current contributions, and future impact.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389006},
doi = {10.1177/13872877251389006},
pmid = {41160443},
issn = {1875-8908},
abstract = {Vascular cognitive impairment (VCI) describes cerebrovascular disease (CeVD)-associated cognitive disorders regardless of pathogenesis, ranging from a prodrome to dementia. Heterogeneity in the etiology and severity of CeVD, and significant co-occurrence with Alzheimer's disease (AD) pathology has hampered investigations. Research into VCI is especially relevant in Asia, where cognitive impairment and dementia, often due to VCI, grows due to rapidly aging populations and high prevalence of vascular risk factors. This manuscript reviewed the rationale, unique positioning, design, methodology, and findings from the HARMONISATION study, a prospective observational study of VCI and AD in multi-ethnic Asians. HARMONISATION aimed to discover and validate novel biomarkers as effective diagnostic and prognostic tools, and translate findings into improved patient care, disease management and treatment-utilizing comprehensive multimodal clinical, neuroimaging, retinal, and blood biomarker data to address critical research gaps such as the etiology and clinical importance of mixed dementia, relationships between AD and CeVD pathology, and challenges of heterogenous CeVD pathology. HARMONIZATION recruited and deeply phenotyped 700 older multi-ethnic Asians with no cognitive impairment, mild cognitive impairment, and dementia for up to 5 years of follow-up. It has yielded developments in biomarker identification, validation, interactions and analysis methods; disease mechanisms and progression; clinical prognostics for VCI and AD; improved patient care and management; and enabled future development of novel interventions in Asians, and globally. An ongoing extension study will allow up to 10 years follow-up to further explore specific modifiable processes of VCI and the contributions of vascular events to cognitive impairment.},
}

@article {pmid41160347,
year = {2025},
author = {Brixner, DI and Zhao, C and Toyosaki, H and Frech, FH and Rosenbloom, MH},
title = {Initial Real-World Evidence for Lecanemab in the United States.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
pmid = {41160347},
issn = {1179-1969},
abstract = {BACKGROUND: Lecanemab is the first anti-amyloid monoclonal antibody with full approval in the US for the treatment of early Alzheimer's disease (AD). This observational study aimed to provide information about patient demographics, clinical characteristics, provider specialty, and lecanemab utilization patterns.

METHODS: This observational study used open administrative claims from the PurpleLab, a database encompassing medical and pharmacy claims derived from diverse sources, such as clearinghouses and Pharmacies. We included patients receiving one or more lecanemab doses between January 6, 2023 and October 31, 2024, and having continuous clinical activity ≥ 6 months prior to the first lecanemab infusion. The observation period ran from the first lecanemab infusion to the latest clinical activity or data availability. Treatment gaps were calculated as the number of gap days in lecanemab supply between consecutive infusions.

RESULTS: Among the study population (n = 4261), mean age was 75.2 years, 77.8% were White, 98.4% lived in urban settings, 81.7% were treated by neurologists, 77.3% had AD, and 31.7% had mild cognitive impairment. Mean follow-up period was 171.1 days. Lecanemab infusions averaged 1.9 per patient per month (SD 1.0), 16.3 days apart (SD 11.0), and 2.8% of patients experienced a treatment interruption ≥90 days.

CONCLUSIONS: Lecanemab utilization followed US FDA-approved prescribing information. Disparities for minority and rural-based populations were observed suggesting opportunities to improve access for underserved populations.},
}

@article {pmid41160319,
year = {2025},
author = {Sarikamis Johnson, B and Ercin, N and Kalkan Cakmak, R and Besli, N and Beker, M and Beker, MC and Celik, U},
title = {Exploring the effects of squalene in the PERK/ATF4/eIF2α/CHOP signalling pathway in an in vitro Alzheimer Disease model and in silico approach.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {300},
pmid = {41160319},
issn = {1573-7365},
support = {123Z925//Scientific and Technological Research Council of Türkiye/ ; 2021-067//University of Health Sciences, Türkiye/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Activating Transcription Factor 4/metabolism ; eIF-2 Kinase/metabolism ; *Signal Transduction/drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Transcription Factor CHOP/metabolism ; *Squalene/pharmacology/therapeutic use ; Unfolded Protein Response/drug effects ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; Amyloid beta-Peptides ; Oxidative Stress/drug effects ; Mesenchymal Stem Cells/drug effects/metabolism ; Cells, Cultured ; Peptide Fragments ; },
abstract = {Recent studies emphasize the pivotal role of endoplasmic reticulum (ER) stress in Alzheimer's disease (AD), highlighting the need for further investigation into this critical link. In response to ER stress, cells increase reactive oxygen species (ROS) production, leading to heightened oxidative stress. This interplay has sparked interest in antioxidant molecules such as squalene (SQ) as potential therapeutic agents. The primary objective of this study was to examine the impact of SQ on the unfolded protein response (UPR) pathway triggered by ER stress in an in vitro AD model. Herein, molecular docking analysis was performed to evaluate SQ interactions with target proteins, followed by in vitro assays. Human bone marrow-derived mesenchymal stem cells were differentiated into neuronal-like cells and characterized via immunostaining. The cells were then exposed to Aβ1-42 toxicity to establish an in vitro AD model. To assess the effects of SQ treatment following Aβ1-42 exposure, UPR-related proteins (BIP, p-PERK, PERK, eIF2α, p-eIF2α, ATF4, CHOP) were analysed by Western blotting; ROS levels were quantified to evaluate oxidative stress, and a TUNEL assay was performed to assess apoptosis. Our findings indicate that SQ alters protein expression within the UPR pathway in the AD experimental model. Notably, amyloid-β levels were significantly reduced in the SQ-treated group (p˂0.001). Furthermore, SQ reduced ROS levels. These results suggest that SQ holds potential as a therapeutic agent for mitigating amyloid-β toxicity.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
Activating Transcription Factor 4/metabolism
eIF-2 Kinase/metabolism
*Signal Transduction/drug effects
Eukaryotic Initiation Factor-2/metabolism
Endoplasmic Reticulum Stress/drug effects
Transcription Factor CHOP/metabolism
*Squalene/pharmacology/therapeutic use
Unfolded Protein Response/drug effects
Reactive Oxygen Species/metabolism
Molecular Docking Simulation
Amyloid beta-Peptides
Oxidative Stress/drug effects
Mesenchymal Stem Cells/drug effects/metabolism
Cells, Cultured
Peptide Fragments

@article {pmid41160288,
year = {2025},
author = {Motamedzadeh, A and Karimzad, Y and Ferdosi, F and Nabavizadeh, F and Rahmati-Dehkordi, F and Dadgostar, E and Aschner, M and Validad, A and Kazemi, B and Tamtaji, OR},
title = {Potential of Benfotiamine in the treatment of neuropsychological disorders.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {26},
pmid = {41160288},
issn = {1573-4978},
mesh = {Humans ; *Thiamine/analogs & derivatives/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Mental Disorders/drug therapy/metabolism ; Signal Transduction/drug effects ; Thiamine Deficiency/drug therapy/metabolism ; },
abstract = {Neuropsychiatric disorders pose significant health challenges. Current drug therapies are often inadequate, highlighting the urgent need for new and effective treatments. Thiamine deficiency has been implicated in the pathophysiology of various neuropsychiatric disorders. In this context, benfotiamine, a synthetic thiamine derivative, has gained increasing attention for its potential therapeutic effects across a range of neuropsychiatric conditions. Emerging evidence supports the neuroprotective effects of benfotiamine, which are mediated through its modulation of diverse cellular and molecular pathways, i.e., Tau phosphorylation, amyloid β, oxidative stress, neuroinflammation, as well as synaptic plasticity via the glycogen synthase kinase-3β (GSK3β) signaling pathway. In this narrative review, we provide a comprehensive overview of the cellular and molecular pathways modulated by benfotiamine in the context of neuropsychiatric disorders. Specifically, we highlight its effects on oxidative stress, inflammatory signaling, mitochondrial function, glucose metabolism, and advanced glycation end-product (AGE) formation, all of which contribute to its neuroprotective and potentially therapeutic properties.},
}

Humans
*Thiamine/analogs & derivatives/pharmacology/therapeutic use
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
*Mental Disorders/drug therapy/metabolism
Signal Transduction/drug effects
Thiamine Deficiency/drug therapy/metabolism

@article {pmid41158654,
year = {2025},
author = {Chiba, T and Hattori, Y and Asakura, K and Sano, Y and Saito, S and Minami, M and Yamamoto, H and Ihara, M},
title = {Taxifolin for prevention of COGnitive impairment (T-COG trial): a study protocol for a randomized, double-blind, placebo-controlled trial.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1686381},
pmid = {41158654},
issn = {2296-861X},
abstract = {BACKGROUND: In 2023 and 2024, the novel anti-β-amyloid antibodies lecanemab and donanemab have been approved for treatment of mild cognitive impairment and mild dementia in several countries, including Japan and the United States. Although they successfully eliminate accumulated β-amyloid, they merely delay cognitive deterioration and do not improve cognitive function. This suggests that β-amyloid elimination is insufficient for cognitive improvement. Therefore, novel treatments with pleiotropic neuroprotective effects are warranted. Taxifolin, a bioactive flavonoid, shows pleiotropic effects, such as inhibition of amyloid-β aggregation and oligomerization and hippocampal neuroinflammation, as well as stimulation of brain lymphatic vessel formation in our previous experimental studies. Furthermore, our preliminary observational study showed that oral administration of taxifolin was associated with cognitive improvement in patients with mild cognitive impairment or mild dementia.

METHODS: This is a randomized, double-blind, placebo-controlled, crossover trial involving 60 patients with mild cognitive impairment or mild dementia. All participants will take 100-mg taxifolin or placebo capsules orally once daily for 12 weeks. The washout period will be 6 weeks. The primary objective is to determine the effect of taxifolin on cognitive impairment using the Montreal Cognitive Assessment. The main secondary objectives are to evaluate the impact of taxifolin on (i) prevention further cognitive decline, as evaluated by changes in the scores for total Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 and trail making test and (ii) changes in white matter hyperintensity volume and number of cerebral microbleeds on brain magnetic resonance imaging.

DISCUSSION: This T-COG trial may provide valuable insights into new therapeutic approaches, considering that taxifolin has multitarget neuroprotection, which could prevent further cognitive decline, along with its highly safe profile and inexpensive cost.

CLINICAL TRIAL REGISTRATION: https://jrct.mhlw.go.jp, jRCTs051250004.},
}

@article {pmid41157961,
year = {2025},
author = {Cruz-Aguilar, MA and Hernández-Arteaga, E and Ramírez-Salado, I and Hernández-González, M and Guevara, MA},
title = {Melatonin reorganizes the sleep EEG spectral power in Alzheimer's disease: a preliminary principal component analysis-based comparison of placebo and treatment effects.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/01616412.2025.2578344},
pmid = {41157961},
issn = {1743-1328},
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaque accumulation, tau pathology, and cortical atrophy, leading to widespread synaptic dysfunction and cognitive decline. Sleep disturbances are highly prevalent in AD and are thought to both reflect and exacerbate underlying neurodegenerative processes. Melatonin, an indoleamine synthesized by the pineal gland, is central to the regulation of circadian rhythms and sleep - wake cycles. In healthy individuals, melatonin enhances non-rapid eye movement (NREM) sleep and attenuates beta activity during wakefulness. In AD populations, it has been associated with improved sleep quality and potential neuroprotective effects against amyloid-related pathology. Electroencephalography (EEG) offers a non-invasive method to monitor neurophysiological changes associated with AD. Principal component analysis (PCA), a dimensionality reduction technique, enables the identification of latent neural patterns within complex EEG data.

METHODS: In this preliminary study, PCA was applied to EEG recordings from eight individuals with mild-to-moderate AD during both wakefulness and sleep under placebo and melatonin conditions. EEG derivations included bipolar (F7-T3, F8-T4, F3-F4, O1-O2) and referential (C3-A1, C4-A2) configurations.

RESULTS: Preliminary PCA suggests that melatonin administration may induce a stage-dependent reorganization of EEG spectral activity, characterized by a relative enhancement of slow-frequency activity and an apparent increase in spectral segregation during NREM sleep.

DISCUSSION: These preliminary findings suggest that melatonin could optimize stage-specific neural dynamics, supporting its therapeutic potential in AD-related sleep disruption.},
}

@article {pmid41156471,
year = {2025},
author = {Zhang, J and Zhang, J},
title = {Natural Small-Molecule Bergapten Ameliorates Amyloid-β Pathology and Neuroinflammation in Alzheimer's Disease.},
journal = {Nutrients},
volume = {17},
number = {20},
pages = {},
doi = {10.3390/nu17203218},
pmid = {41156471},
issn = {2072-6643},
support = {2022QH2300//Fujian Medical University/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Amyloid beta-Peptides/metabolism ; Microglia/drug effects/metabolism ; Molecular Docking Simulation ; *Neuroinflammatory Diseases/drug therapy ; Disease Models, Animal ; Male ; Maze Learning/drug effects ; MAP Kinase Signaling System/drug effects ; Memory/drug effects ; *Anti-Inflammatory Agents/pharmacology ; },
abstract = {BACKGROUND: The pathogenesis of Alzheimer's disease (AD) is complex, and effective treatments remain elusive. Growing evidence suggests that dietary factors may play a significant role in preventing or alleviating AD. Bergapten (BG), a natural compound with anti-inflammatory properties, has been studied; however, its specific role in neuroinflammation and AD pathogenesis remains unclear.

METHODS: Through public databases and bioinformatics tools, the possible molecular mechanisms of BG's effects on AD were analyzed. Six-month-old 5×FAD mice underwent intragastric administration of BG for 30 consecutive days. Learning and memory abilities were assessed using the novel object recognition (NOR) test and the Morris water maze (MWM) test. Immunofluorescence staining, Western blot and q-PCR was conducted to assess the underlying mechanisms. In vitro experiments used Aβ-stimulated BV2 microglial cells for BG intervention.

RESULTS: Bioinformatics analysis revealed the MAPK signaling pathway as the top-ranked pathway. Molecular docking studies further demonstrated strong binding interactions between BG and key proteins within the MAPK pathway. In behavioral studies, NOR test and MWM test demonstrated that BG treatment improved learning and memory abilities in 5×FAD mice. Additionally, BG treatment significantly reduced Aβ deposition, pro-inflammatory cytokine levels, and inhibited excessive microglial activation in these mice. Consistent with in vivo findings, BG effectively decreased pro-inflammatory cytokines in Aβ-stimulated BV2 microglial cells. Mechanistic studies revealed that BG attenuates neuroinflammatory responses by inhibiting the MAPK signaling pathway both in vivo and in vitro.

CONCLUSIONS: Our findings suggest that BG mitigates AD pathological features by suppressing MAPK-mediated neuroinflammation and represents a promising natural small molecule for the prevention and treatment of AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
*Amyloid beta-Peptides/metabolism
Microglia/drug effects/metabolism
Molecular Docking Simulation
*Neuroinflammatory Diseases/drug therapy
Disease Models, Animal
Male
Maze Learning/drug effects
MAP Kinase Signaling System/drug effects
Memory/drug effects
*Anti-Inflammatory Agents/pharmacology

@article {pmid41155570,
year = {2025},
author = {Atanasova, M},
title = {Small-Molecule Inhibitors of Amyloid Beta: Insights from Molecular Dynamics-Part B: Natural Compounds.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101457},
pmid = {41155570},
issn = {1424-8247},
support = {Grant No BG16RFPR002-1.014-0018//the Centre of Excellence in Informatics and ICT funded by the Research, Innovation and Digitalization for Smart Transformation Programme 2021-2027 and co-financed by the European Union/ ; agreement D01-98/26.06.2025//the National Road Map/ ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline. Its key pathological hallmarks include extracellular amyloid plaques composed of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Although numerous studies have investigated the complex pathology of AD, its underlying mechanisms remain incompletely understood. The amyloid cascade hypothesis continues to be the leading model of AD pathogenesis. It suggests that Aβ aggregation is the initial trigger of neurotoxicity, setting off a cascade of pathological events including inflammation, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, and, ultimately, dementia. Molecular dynamics (MD) is a powerful tool in structure-based drug design (SBDD). By simulating biomolecular motions at the atomic level, MD provides unique insights into molecular properties, functions, and inhibition mechanisms-insights often inaccessible through other experimental or computational techniques. When integrated with experimental data, MD further deepens our understanding of molecular interactions and biological processes. Natural compounds, known for their pleiotropic pharmacological activities, favorable safety profiles, and general tolerability (despite occasional side effects), are increasingly explored for their potential in both the treatment and prevention of various diseases, including AD. In this review, we summarize current findings from MD simulations of natural compounds with anti-amyloidogenic potential. This work builds upon our previous publication, which focused on endogenous compounds and repurposed drugs. The review is structured as follows: an overview of the amyloid cascade hypothesis; a discussion of Aβ oligomeric structures and their stabilizing interactions; a section on molecular dynamics, including its challenges and future directions; and a comprehensive analysis of the inhibitory mechanisms of natural compounds, categorized by their shared structural features.},
}

@article {pmid41155541,
year = {2025},
author = {Perez, DM},
title = {α1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline Non-Selective Blockers.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101425},
pmid = {41155541},
issn = {1424-8247},
support = {RO1AG066627/GF/NIH HHS/United States ; },
abstract = {Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α1-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α1-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.},
}

@article {pmid41155525,
year = {2025},
author = {Lin, GB and Liu, HH and Kuo, YY and Chen, YM and Hsu, FT and Wang, YW and Kung, Y and Ching, C and Chao, CY},
title = {Thermal Cycling Stimulation via Nasal Inhalation Attenuates Aβ25-35-Induced Cognitive Deficits in C57BL/6 Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010236},
pmid = {41155525},
issn = {1422-0067},
support = {NSTC 113-2112-M-002-024//National Science and Technology Council/ ; NSTC 112-2112-M-002-033//National Science and Technology Council/ ; MOST 110-2112-M-002-004//Ministry of Science and Technology/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice ; Mice, Inbred C57BL ; *Cognitive Dysfunction/therapy/metabolism/chemically induced ; Male ; *Peptide Fragments/toxicity ; Hippocampus/metabolism ; Disease Models, Animal ; Alzheimer Disease/therapy/metabolism ; *Hyperthermia, Induced/methods ; Administration, Inhalation ; Maze Learning ; },
abstract = {Alzheimer's disease (AD) remains a significant public health challenge, with current treatments limited partly due to the difficulty of delivering therapeutics across the blood-brain barrier (BBB). The nose-to-brain (N-2-B) pathway offers a promising alternative to circumvent the BBB, but no drugs have yet been clinically applied via this route for AD. Mild stress is thought to activate intrinsic protective mechanisms against neurodegeneration, but traditional methods lack specificity and practicality. To address this, we propose the inhalation of mildly heated air as thermal stimulation, which utilizes the N-2-B pathway to induce mild stress and stimulate cerebral activity. This study employs thermal cycling-hyperthermia (TC-HT) in developing thermal cycling-stimulation via nasal inhalation (TCSNI), providing cyclic stimulation to maintain pathway activity while minimizing thermal injury. In C57BL/6 mice, TCSNI showed no adverse olfactory effects. In β-amyloid (Aβ)-treated mice, TCSNI significantly enhanced cognitive performance in Y-maze and novel object recognition (NOR) assessments, suggesting cognitive improvement. Mice hippocampal protein analyses indicated a reduction in Aβ accumulation, alongside increased expression of heat shock protein 70 (HSP70), insulin-degrading enzyme (IDE), and phosphorylated Akt (p-Akt). These results suggest that N-2-B-delivered TCSNI effectively modulates protein expression and enhances cognitive function, highlighting its potential for further exploration in AD treatment.},
}

Animals
*Amyloid beta-Peptides/metabolism/toxicity
Mice
Mice, Inbred C57BL
*Cognitive Dysfunction/therapy/metabolism/chemically induced
Male
*Peptide Fragments/toxicity
Hippocampus/metabolism
Disease Models, Animal
Alzheimer Disease/therapy/metabolism
*Hyperthermia, Induced/methods
Administration, Inhalation
Maze Learning

@article {pmid41155356,
year = {2025},
author = {Trifonova, EA and Pashchenko, AA and Ivanov, RA and Kochetov, AV and Lashin, SA},
title = {Genetic and Pathogenic Overlaps Between Autism Spectrum Disorder and Alzheimer's Disease: Evolutionary Features and Opportunities for Drug Repurposing.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010066},
pmid = {41155356},
issn = {1422-0067},
mesh = {*Autism Spectrum Disorder/genetics/drug therapy ; Humans ; *Alzheimer Disease/genetics/drug therapy/metabolism ; *Drug Repositioning ; Gene Regulatory Networks ; TOR Serine-Threonine Kinases/metabolism/genetics ; Genetic Predisposition to Disease ; Evolution, Molecular ; Signal Transduction ; },
abstract = {Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelopmental and neurodegenerative disorders, respectively. While exome sequencing is routinely employed during the early stages of ASD diagnosis, it rarely influences therapeutic strategies. To address this gap, we have reconstructed and analyzed the gene networks linking autism spectrum disorders, Alzheimer's disease, and mTOR signaling. In addition, we have performed a phylostratigraphic analysis that reveals similarities and differences in the evolution of both ASD and Alzheimer's disease predisposition genes. We have shown that almost half of the genes predisposing to autism and two-fifths of the genes predisposing to Alzheimer's disease are directly related to the mTOR signaling pathway. Analysis of Phylostratigraphic Age Index (PAI) value distributions revealed a significant enrichment of evolutionarily ancient genes in both ASD- and AD-related gene sets. When studying the distribution of ASD predisposition genes by Divergence Index (DI) values, a significant enrichment with genes having extremely low DI = 0 has been found. Such low DI values indicate that most likely these genes are under stabilizing selection. Using the ANDVisio tool, both pharmacological and natural mTOR regulators with potential for ASD treatment were selected, such as propofol, dexamethasone, celecoxib, statins, berberine, resveratrol, quercetin, myricetin, mio-inositol, and several amino acids.},
}

*Autism Spectrum Disorder/genetics/drug therapy
Humans
*Alzheimer Disease/genetics/drug therapy/metabolism
*Drug Repositioning
Gene Regulatory Networks
TOR Serine-Threonine Kinases/metabolism/genetics
Genetic Predisposition to Disease
Evolution, Molecular
Signal Transduction

@article {pmid41155218,
year = {2025},
author = {Lee, J and Lee, E and Kwon, H and Moon, S and Bae, HJ and Hwang, JH and Cho, GH and Kong, H and Park, MH and Kim, SK and Kim, DH and Jung, JW},
title = {Synaptic Plasticity-Enhancing and Cognitive-Improving Effects of Standardized Ethanol Extract of Perilla frutescens var. acuta in a Scopolamine-Induced Mouse Model.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209925},
pmid = {41155218},
issn = {1422-0067},
support = {S3400191//Ministry of SMEs and Startups/ ; },
mesh = {Animals ; Scopolamine/toxicity ; Mice ; Male ; *Plant Extracts/pharmacology/chemistry ; *Perilla frutescens/chemistry ; *Neuronal Plasticity/drug effects ; Disease Models, Animal ; Mice, Inbred ICR ; Hippocampus/drug effects/metabolism ; Long-Term Potentiation/drug effects ; Ethanol/chemistry ; *Cognition/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; *Cognitive Dysfunction/drug therapy/chemically induced ; Maze Learning/drug effects ; },
abstract = {In our previous study, we demonstrated that a standardized ethanol extract of Perilla frutescens var. acuta (PE) alleviates memory deficits in an Alzheimer's disease mouse model by inhibiting amyloid β (Aβ) aggregation and promoting its disaggregation. However, the extent to which PE exerts additional cognitive benefits independent of Aβ pathology remained unclear. Here, we aimed to evaluate the effects of PE on synaptic plasticity and learning and memory functions. Male ICR mice were used, and cognitive impairment was induced by scopolamine administration. PE was orally administered at doses determined from previous studies, and cognitive performance was assessed using the passive avoidance, Y-maze, and Morris water maze tests. In parallel, hippocampal slices were employed to examine the effects of PE on synaptic plasticity. PE (100 and 300 μg/mL) significantly enhanced long-term potentiation (LTP) in a concentration-dependent manner without altering basal synaptic transmission. This facilitation of LTP was blocked by scopolamine (1 μM), a muscarinic acetylcholine receptor (mAChR) antagonist, and IEM-1460 (50 μM), a calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) inhibitor, indicating the involvement of mAChR and CP-AMPAR pathways. In vivo, PE (100, 250, and 500 mg/kg) treatment improved memory performance across all behavioral tasks and upregulated hippocampal synaptic proteins including GluN2B, PSD-95, and CaMKII. Collectively, these results demonstrate that PE ameliorates scopolamine (1 mg/kg)-induced cognitive impairment by enhancing synaptic plasticity, likely through modulation of mAChR, CP-AMPAR, and NMDA receptor signaling. These findings highlight the therapeutic potential of PE for memory deficits associated with cholinergic dysfunction.},
}

Animals
Scopolamine/toxicity
Mice
Male
*Plant Extracts/pharmacology/chemistry
*Perilla frutescens/chemistry
*Neuronal Plasticity/drug effects
Disease Models, Animal
Mice, Inbred ICR
Hippocampus/drug effects/metabolism
Long-Term Potentiation/drug effects
Ethanol/chemistry
*Cognition/drug effects
Receptors, N-Methyl-D-Aspartate/metabolism
*Cognitive Dysfunction/drug therapy/chemically induced
Maze Learning/drug effects

@article {pmid41155192,
year = {2025},
author = {Kowalczyk, T and Muskała, M and Piekarski, J and Kowalski, M and Staszewski, M and Konuklugil, B and Rijo, P and Sitarek, P},
title = {Therapeutic Promise and Biotechnological Prospects of Dendroaspis polylepis Venom Proteins: Mambalgins, Fasciculins, and Dendrotoxins.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209895},
pmid = {41155192},
issn = {1422-0067},
mesh = {Humans ; Animals ; *Snake Venoms/chemistry/therapeutic use/pharmacology ; *Neurotoxins/therapeutic use/pharmacology/chemistry ; Neoplasms/drug therapy ; Biotechnology/methods ; },
abstract = {Animal toxins contain various bioactive peptides and proteins which have evolved to interact in specific ways. As such, they are a good starting point for developing new drugs and vaccines. This paper examines three natural neurotoxins derived from the black mamba (Dendroaspis polylepis), which show significant pharmacological potential: mambalgins, fasciculins and dendrotoxins. All three may be of value in the treatment of pain, cancer and neurodegenerative disease. Mambalgins provide similar pain relief to opioids but without the risk of addiction; they act by selectively blocking acid-sensitive ion channels (ASICs), especially ASIC1a. Thanks to this inhibitory activity they also demonstrate selective activity against glioblastoma, melanoma and leukemia cells as innovative anticancer drugs. Fasciculins are very strong inhibitors of acetylcholinesterase (AChE) and hence offer promise in multi-target drugs and as treatments for treating Alzheimer's disease. Dendrotoxins such as DTX-K and DTX-I are able to modulate neuronal excitability and synaptic transmission by blocking voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.6); both have been shown to be effective against cancer cells, and to influence the cardiovascular, immune, and digestive systems. Recent advances in recombinant biotechnology and protein engineering have allowed their safe production with increased therapeutic value. The review examines the translational potential of D. polylepis venom proteins and highlights the need for additional preclinical research on bioactive molecules of toxin origin.},
}

Humans
Animals
*Snake Venoms/chemistry/therapeutic use/pharmacology
*Neurotoxins/therapeutic use/pharmacology/chemistry
Neoplasms/drug therapy
Biotechnology/methods

@article {pmid41155149,
year = {2025},
author = {Frei, M and Wirawan, R and Wein, T and Bracher, F},
title = {Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209855},
pmid = {41155149},
issn = {1422-0067},
support = {project ID: 325871075-SFB1309//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) with funds from SFB1309 (Chemical Biology of Epigenetic Modifications)/ ; },
mesh = {*Sirtuin 2/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; Humans ; Structure-Activity Relationship ; *Histone Deacetylase Inhibitors/chemistry/pharmacology ; },
abstract = {Selective and potent inhibitors of the NAD[+]-dependent deacetylase Sirt2 represent a valuable epigenetic strategy for the treatment of currently incurable diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, and multiple sclerosis. Guided by molecular docking and MM/GBSA validation studies, a lead structure-based hybridization strategy was developed, resulting in a series of very effective Sirt2 inhibitors. With RW-93, we present a highly potent and subtype selective Sirt2 inhibitor (IC50 = 16 nM), which as a next generation SirReal-type inhibitor significantly surpasses established Sirt2 inhibitors and contributes to the extension of the current SAR profile. The structural modification strategy employed in this study proved to be highly promising, resulting in the identification of the most potent low-molecular-weight Sirt2 inhibitor reported to date, providing a promising target for further medicinal chemistry-driven SAR studies.},
}

*Sirtuin 2/antagonists & inhibitors/chemistry/metabolism
Molecular Docking Simulation
Humans
Structure-Activity Relationship
*Histone Deacetylase Inhibitors/chemistry/pharmacology

@article {pmid41155106,
year = {2025},
author = {Rahman, S and Rahman, MM and Bhatt, S and Sundararajan, R and Faezipour, M},
title = {NeuroNet-AD: A Multimodal Deep Learning Framework for Multiclass Alzheimer's Disease Diagnosis.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {12},
number = {10},
pages = {},
doi = {10.3390/bioengineering12101107},
pmid = {41155106},
issn = {2306-5354},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia. This disease significantly impacts cognitive functions and daily activities. Early and accurate diagnosis of AD, including the preliminary stage of mild cognitive impairment (MCI), is critical for effective patient care and treatment development. Although advancements in deep learning (DL) and machine learning (ML) models improve diagnostic precision, the lack of large datasets limits further enhancements, necessitating the use of complementary data. Existing convolutional neural networks (CNNs) effectively process visual features but struggle to fuse multimodal data effectively for AD diagnosis. To address these challenges, we propose NeuroNet-AD, a novel multimodal CNN framework designed to enhance AD classifcation accuracy. NeuroNet-AD integrates Magnetic Resonance Imaging (MRI) images with clinical text-based metadata, including psychological test scores, demographic information, and genetic biomarkers. In NeuroNet-AD, we incorporate Convolutional Block Attention Modules (CBAMs) within the ResNet-18 backbone, enabling the model to focus on the most informative spatial and channel-wise features. We introduce an attention computation and multimodal fusion module, named Meta Guided Cross Attention (MGCA), which facilitates effective cross-modal alignment between images and meta-features through a multi-head attention mechanism. Additionally, we employ an ensemble-based feature selection strategy to identify the most discriminative features from the textual data, improving model generalization and performance. We evaluate NeuroNet-AD on the Alzheimer's Disease Neuroimaging Initiative (ADNI1) dataset using subject-level 5-fold cross-validation and a held-out test set to ensure robustness. NeuroNet-AD achieved 98.68% accuracy in multiclass classification of normal control (NC), MCI, and AD and 99.13% accuracy in the binary setting (NC vs. AD) on the ADNI dataset, outperforming state-of-the-art models. External validation on the OASIS-3 dataset further confirmed the model's generalization ability, achieving 94.10% accuracy in the multiclass setting and 98.67% accuracy in the binary setting, despite variations in demographics and acquisition protocols. Further extensive evaluation studies demonstrate the effectiveness of each component of NeuroNet-AD in improving the performance.},
}

@article {pmid41154564,
year = {2025},
author = {Wei, C and Chen, X and Sun, M and Cao, J and Liao, D and Cheng, Z and Wang, H},
title = {α-Asarone Maintains Protein Homeostasis Through SKN-1-Mediated Proteasome and Autophagy Pathways to Mitigate Aβ-Associated Toxicity in Caenorhabditis elegans.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/antiox14101255},
pmid = {41154564},
issn = {2076-3921},
support = {32370420//National Natural Science Foundation of China/ ; 31670347//National Natural Science Foundation of China/ ; 23ZR1467200//Natural Science Foundation of Shanghai/ ; },
abstract = {Acorus tatarinowii Schott (A. tatarinowii), a traditional Chinese medicine, has been widely used in the treatment of dementia, particularly AD. α-Asarone is the main active component of A. tatarinowii oil, and its neuroprotective effects and underlying molecular mechanism in AD remain unclear. In this study, we utilized different transgenic Caenorhabditis elegans (C. elegans) AD models to investigate the neuroprotective mechanism of α-asarone in vivo. Our findings revealed that α-asarone significantly ameliorated Aβ- and tau-induced phenotypic abnormalities, including deficits in chemotaxis-related learning, hyposensitivity to exogenous serotonin, and impaired neuronal integrity. Furthermore, the α-asarone treatment effectively reduced Aβ-induced oxidative stress. Mechanistically, α-asarone reduced Aβ accumulation and maintained protein homeostasis by stimulating proteasome degradation and autophagy in an SKN-1/Nrf2-dependent manner. Our study highlights the potential of α-asarone as an SKN-1/Nrf2 activator and its capability to facilitate proteostasis, supporting its therapeutic potential for AD treatment.},
}

@article {pmid41154171,
year = {2025},
author = {Zou, J and Liao, R and Zhang, W and Kuang, Z},
title = {Acupuncture Modulation of the Lung-Brain Axis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.},
journal = {Brain sciences},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/brainsci15101076},
pmid = {41154171},
issn = {2076-3425},
support = {2025A1515012049//Natural Science Foundation of Guangdong Province/ ; 20251096//the Research Project of the Traditional Chinese Medicine Bureau of Guangdong Province/ ; 2023A1515110788//Basic and Applied Basic Research Foundation of Guangdong Province/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and an impaired quality of life, for which no curative treatment is currently available. Recent research indicates that chronic pulmonary conditions-including chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA)-exhibit significant epidemiological associations with AD pathogenesis, suggesting that the lung-brain axis may contribute to AD development. Acupuncture, a core TCM intervention, shows promise for modulating multisystem functions and enhancing cognitive performance. This review synthesizes the current evidence regarding pulmonary diseases influencing AD through the lung-brain axis, elucidates potential mechanisms by which acupuncture may modulate pulmonary function and mitigate AD pathology, and explores future directions for lung-brain axis-targeted acupuncture interventions. Our overarching aim is to propose integrative, evidence-based strategies that combine Chinese and Western medicine for the prevention and management of AD.},
}

@article {pmid41153730,
year = {2025},
author = {Danesin, L and D'Este, G and Barresi, R and Piazzalunga, E and Di Garbo, A and Giustiniani, A and Semenza, C and Bottini, G and Oliveri, M and Burgio, F},
title = {Preliminary Evidence of Biological and Cognitive Efficacy of Prismatic Adaptation Combined with Cognitive Training on Patients with Mild Cognitive Impairment.},
journal = {Biomedicines},
volume = {13},
number = {10},
pages = {},
doi = {10.3390/biomedicines13102447},
pmid = {41153730},
issn = {2227-9059},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {Background/Objectives: This study evaluated a novel rehabilitation tool that combines prismatic adaptation (PA) and cognitive training through serious games (SGs) in patients with mild cognitive impairment (MCI) due to prodromal Alzheimer's dementia or consequent to Parkinson's disease. While non-pharmacological interventions have been shown to improve cognition or delay dementia onset, their underlying neurobiological mechanisms, such as brain plasticity, remain unclear. Leveraging studies suggesting neuromodulatory effects of PA, we investigated whether the combined PA+SGs treatment could influence plasticity-related mechanisms, assessed through brain-derived neurotrophic factor (BDNF) serum levels, compared to cognitive training with only SGs and standard cognitive rehabilitation (SCR). Methods: Twenty three MCI patients were randomized into three intervention groups: PA+SGs (experimental group), SG-only (control group), and SCR (control group), completing ten treatment sessions. Patients underwent neuropsychological assessments and blood sampling pre- and post-treatment. Results: At baseline, demographic, clinical, and biological characteristics were comparable across groups. Post-treatment, though differences from control groups were not statistically significant, the PA+SGs group showed significant within-group improvements in memory, with trend-level changes also in executive function and visuospatial abilities, which, however, did not reach the significance threshold. Notably, only the PA+SGs group exhibited increased BDNF levels, which positively correlated with memory and language performance. Conclusions: Our findings suggest that combining PA with cognitive training may enhance cognitive functioning in MCI patients, yielding results comparable to SCR. Furthermore, PA appears to enhance neuroplasticity mechanisms that may support the behavioral improvements observed in cognitive training. Future research should validate these findings and further explore the relationship between cognitive impairment and its rehabilitation, while also considering the underlying neurobiological mechanisms.},
}

@article {pmid41152946,
year = {2025},
author = {Bali, ZK and Bruszt, N and Göntér, K and Hernádi, I},
title = {Differential cognitive enhancer effects of acetylcholinesterase inhibitors and memantine on age-related deficits in vigilance and sustained attention: a preclinical validation study.},
journal = {Behavioral and brain functions : BBF},
volume = {21},
number = {1},
pages = {35},
pmid = {41152946},
issn = {1744-9081},
support = {KK/492/2019//Gedeon Richter Plc., Budapest, Hungary/ ; RRF-2.3.1-21-2022-00015//National Research, Development and Innovation Office/ ; K 143816//National Research, Development, and Innovation Office of the Hungarian Government/ ; },
mesh = {Animals ; *Memantine/pharmacology ; Donepezil/pharmacology ; *Cholinesterase Inhibitors/pharmacology ; Galantamine/pharmacology ; *Attention/drug effects ; Rats ; Male ; *Nootropic Agents/pharmacology ; Psychomotor Performance/drug effects ; Reaction Time/drug effects ; *Aging/drug effects/psychology ; Cognition/drug effects ; *Arousal/drug effects ; Indans/pharmacology ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: The psychomotor vigilance task (PVT) is a cognitive test commonly used to measure sustained attention and vigilance in humans in healthy and diseased states. Here, we aimed to utilize a recently designed rat version of the PVT to assess potential cognitive enhancer effects of various pharmacological compounds in a natural model of age-related cognitive decline. Therefore, we treated aged rats (> 28 months old) with different doses of three approved Alzheimer's disease drugs: donepezil, galantamine, and memantine.

RESULTS: Aged rats made significantly slower responses to the cue stimuli compared to young animals and fewer correct responses, mainly because of an increased number of missed trials (i.e., when the trial was not initiated by the rat). Donepezil improved the performance of aged rats by accelerating their responses at a dose of 0.03 mg/kg. However, galantamine treatment showed no beneficial effects on either reaction time or the number of correct trials. Furthermore, both donepezil (0.3 and 1.0 mg/kg) and galantamine (3.0 mg/kg) increased the reaction time and number of missed trials at high doses. Memantine did not affect the reaction time of aged rats, but it increased the number of correct responses at 0.1 and 0.3 mg/kg doses.

CONCLUSIONS: Here, we showed that PVT is suitable for addressing pharmacological effects on various cognitive domains in a single behavioral paradigm. Our findings also indicate that different cognitive enhancer compounds (even when their targets are thought to be the same) may differentially influence distinct cognitive domains and modulate task performance.},
}

Animals
*Memantine/pharmacology
Donepezil/pharmacology
*Cholinesterase Inhibitors/pharmacology
Galantamine/pharmacology
*Attention/drug effects
Rats
Male
*Nootropic Agents/pharmacology
Psychomotor Performance/drug effects
Reaction Time/drug effects
*Aging/drug effects/psychology
Cognition/drug effects
*Arousal/drug effects
Indans/pharmacology
Cognitive Dysfunction/drug therapy

@article {pmid41152341,
year = {2025},
author = {Fujii, K and Koshidaka, Y and Yanagibashi, Y and Adachi, M and Matsuo, M and Kimura, K and Saito, T and Saido, TC and Takao, K},
title = {Ovariectomy attenuates phenotypes related to Alzheimer's disease in a preclinical mouse model and in C57BL/6 J mice.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {36995},
pmid = {41152341},
issn = {2045-2322},
support = {22H04922//Japan Society for the Promotion of Science/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology/physiopathology ; *Ovariectomy ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred C57BL ; Phenotype ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Transgenic ; Behavior, Animal ; Mutation ; Amyloid beta-Peptides/metabolism ; Fear ; Anxiety ; Gene Knock-In Techniques ; Memory ; },
abstract = {Women are at higher risk for Alzheimer's disease (AD) than men and hormonal changes during perimenopause are considered a risk factor. The relationship between ovarian hormones and AD has been explored using AD animal models, especially through ovariectomy (OVX) in established AD models. The link between early-stage AD and ovarian hormones, however, remains unclear, largely due to the lack of suitable animal models. Appropriate models for studying early-stage AD pathology, treatment, and prevention are critically needed. The App knock-in mouse model, which carries a single amyloid precursor protein (App) gene mutation, effectively reproduces early amyloid AD pathology. To elucidate the relationship between ovarian hormone deficiency and the behavioral phenotypes of a preclinical AD model, we applied a comprehensive behavioral test battery to this mouse model with bilateral OVX. The App mutation reduced anxiety-like behavior and impaired performance in the fear memory task. OVX restored the anxiety-like behavior of the App mutation mice to a level comparable to that in wild-type (WT) mice. Furthermore, OVX enhanced performance in a fear memory task in both genotypes and reduced amyloid-β staining in WT mice. Together, these findings suggest that OVX attenuates AD-related phenotypes in a preclinical AD model and in C57BL/6 J WT mice.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology/physiopathology
*Ovariectomy
Disease Models, Animal
Female
Mice
Mice, Inbred C57BL
Phenotype
Amyloid beta-Protein Precursor/genetics/metabolism
Mice, Transgenic
Behavior, Animal
Mutation
Amyloid beta-Peptides/metabolism
Fear
Anxiety
Gene Knock-In Techniques
Memory

@article {pmid41152189,
year = {2025},
author = {Snyder, A and Samra, K and Wu, T and Russell, LL and Farren, J and Crook, J and Haselhuhn, T and Porter, K and Szabo, M and Duckett, A and Lin, F and Danielian, L and Traynor, BJ and Scholz, SW and Boeve, BF and Rosen, HJ and Rohrer, JD and Kwan, JY},
title = {Integrating a motor domain enhances disease severity scales in an FTD-ALS spectrum cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70786},
doi = {10.1002/alz.70786},
pmid = {41152189},
issn = {1552-5279},
support = {U01AG045390//The National Institute on Aging/ ; U54NS092089//The National Institute on Aging/ ; U19AG063911//The National Institute on Aging/ ; //The Intramural Research Program of the National Institutes of Health/ ; /NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Male ; *Severity of Illness Index ; Female ; *Frontotemporal Dementia/diagnosis/physiopathology ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Aged ; Longitudinal Studies ; Cohort Studies ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)-derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures.

METHODS: The CDR plus National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD), CDR + NACC FTLD-M (Motor), and Multidomain Impairment Rating (MIR) scores and motor measures were determined and correlated in 242 participants.

RESULTS: Both CDR + NACC FTLD-M and MIR showed increased disease severity scores and correlated with motor measures. These findings were held in 81 amyotrophic lateral sclerosis (ALS) participants and correlated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Including a motor domain required fewer study participants in a simulated clinical trial sample size calculation.

DISCUSSION: With a motor domain, CDR + NACC FTLD-M and MIR improve disease severity classification and correlate with quantitative motor assessments. This addition more fully captures the extent of symptoms across the FTD-ALS spectrum and improves clinical trial efficiency.

HIGHLIGHTS: CDR + NACC FTLD-M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.},
}

Humans
Male
*Severity of Illness Index
Female
*Frontotemporal Dementia/diagnosis/physiopathology
Middle Aged
*Amyotrophic Lateral Sclerosis/diagnosis/physiopathology
Aged
Longitudinal Studies
Cohort Studies
Neuropsychological Tests

@article {pmid41151846,
year = {2025},
author = {Kuzuya, A and Ohara, T and Akamatsu, N},
title = {Pathogenesis of comorbid epilepsy in Alzheimer's disease and use of perampanel, an ampa receptor inhibitor.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737175.2025.2581758},
pmid = {41151846},
issn = {1744-8360},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and epilepsy frequently co-occur and are risk factors for each other's onset. In patients with AD-comorbid epilepsy, seizure control with appropriate anti-seizure medications (ASMs) is crucial, yet no established treatment guidelines exist. Recent studies indicate that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are involved in the pathogenesis of both diseases. Perampanel, an AMPAR antagonist, has been approved as an ASM.

AREAS COVERED: This review explains the relationship between AD and epilepsy and discusses the involvement of AMPARs. Furthermore, it focuses on and presents opinions regarding the role of AMPAR inhibitors in the treatment of AD-comorbid epilepsy. The authors searched clinical studies that were published and identifiable in PubMed and Scopus (Jan 2015-Dec 2024) including the terms 'Alzheimer's disease,' or 'dementia,' with 'epilepsy' or 'seizure'.

EXPERT OPINION: Considering the hypothesis that AD and epilepsy are linked, creating a cycle that progresses both diseases via AMPARs, AMPAR inhibition may have beneficial effects in treatment of epilepsy in AD. Although evidence is limited, studies of perampanel have demonstrated symptomatic improvement in patients with AD-comorbid epilepsy. Perampanel may be particularly useful for specific subgroups of patients with AD-comorbid epilepsy, such as those with myoclonus, sleep disturbances, or poor medication adherence.},
}

@article {pmid41151285,
year = {2025},
author = {Song, J and Ding, X and Li, M and Xin, Y and Lu, Y and Yang, X and Lu, X},
title = {N[6]-methyladenosine reader YTHDF1 mediates neuronal apoptosis induced by aluminum via m[6]A/Bcl-2 manner.},
journal = {Ecotoxicology and environmental safety},
volume = {306},
number = {},
pages = {119270},
doi = {10.1016/j.ecoenv.2025.119270},
pmid = {41151285},
issn = {1090-2414},
abstract = {Aluminum (Al) has emerged as a pervasive environmental and industrial risk factor for cognitive impairment and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Nowadays, N6-methyladenosine (m[6]A) modification mechanism contributing to aluminum toxicity is gradually gaining attention. m[6]A modification determines the fate of RNA through m[6]A "readers". Novel findings indicate that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1, a kind of "readers") participates in various pathological processes induced by some toxic chemicals. Here, we investigated the function of YTHDF1 in neuronal apoptosis induced by aluminum and explored the molecular mechanisms. We first observed the YTHDF1 expression both in vivo and in vitro neuronal apoptosis model induced by aluminum, as well as the reversal effect of YTHDF1 overexpression by lentivirus transfection in vitro. Further, we explored Bcl-2 as a target gene of YTHDF1 and probed their m[6]A modification manner and molecular mechanism using RIP assay, Me-RIP assay, and Actinomycin D (ActD) assay. Finally, we examined the regulatory role of YTHDF1/m[6]A/Bcl-2 axis in aluminum neurotoxicity in vitro and in vivo. Functionally, Al(mal)3 treatment decreased YTHDF1 expression, which negatively regulates apoptosis via m[6]A modification manner. Mechanistically, Bcl-2 acted as the target of YTHDF1, and YTHDF1 regulated Bcl-2 by enhancing its mRNA stability. Collectively, Al(mal)3 treatment inhibited the YTHDF1/m[6]A/Bcl-2 axis, thereby promoting neuronal apoptosis and subsequent cognitive impairment. This study provides a novel protective strategy against aluminum toxicity.},
}

@article {pmid41151129,
year = {2025},
author = {Yang, F and Guo, Q and Chen, M and Wang, W and Chen, X and Zhang, S and Bian, H and Li, J and Jiao, Z and Wang, Q and Xiong, W and Huang, YY and Liu, Y and Xu, C and Huang, L},
title = {Discovery of novel 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one derivatives as PDE2 inhibitors with Alzheimer's disease therapeutic potential.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 1},
pages = {118302},
doi = {10.1016/j.ejmech.2025.118302},
pmid = {41151129},
issn = {1768-3254},
abstract = {Phosphodiesterase 2 (PDE2), a dual-substrate cyclic nucleotide hydrolase, represents a potential therapeutic target for cognitive impairment. This study aims to develop 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one-based PDE2 inhibitors with favorable drug-like properties for the treatment of Alzheimer's disease. Through scaffold hopping and cocrystal structure analysis, compound 14c was identified as an effective PDE2 inhibitor (IC50 = 0.6 μM, aqueous solubility = 60.36 μg/mL). Moreover, 14c demonstrated favorable hepatic microsomal stability, pharmacokinetic properties (t1/2 = 4.4 h, F% = 95.66 %) and promising safety both in vitro and in vivo. In the OKA-induced AD mice models, administration of 14c significantly improved memory deficits and cognitive impairment. Molecular mechanism studies revealed that the neuroprotective effects of 14c were mediated through the PKA/CREB/BDNF signaling pathway. Collectively, these findings represent significant advances in developing PDE2 inhibitors with favorable drug-like properties and establish a solid foundation for their therapeutic application in AD.},
}

@article {pmid41149051,
year = {2025},
author = {Valdez Gayosso, N and Omaña Covarrubias, A and Nez Castro, AT and López Pontigo, L and Acuña Gurrola, MDR and Pimentel Pérez, BM},
title = {The Effect of Bacteria Modulation with Probiotic Consumption in Neurodegeneration During Aging: A Narrative Review of the Literature.},
journal = {Diseases (Basel, Switzerland)},
volume = {13},
number = {10},
pages = {},
doi = {10.3390/diseases13100317},
pmid = {41149051},
issn = {2079-9721},
support = {NA//Universidad Autónoma del Estado de Hidalgo/ ; },
abstract = {Aging is the result of the accumulation of a great variety of molecular and cellular damage over time. During aging, the brain undergoes changes and diseases such as depression, dementia, anxiety, Alzheimer's, delirium, behavioral disorders and aggression, and prolonged mourning, among others, appear. The gut-brain axis suggests that the gut and the brain have a bidirectional communication, so it is important to maintain proper intestinal health to strengthen the neurological changes of this age group. The intestinal microbiota is a dynamic and highly complex ecosystem of microorganisms residing in the gastrointestinal tract. The bidirectional and dynamic communication between the homeostatic systems, such as the endocrine and immune systems, as well as the nervous system, allow us to face problems associated with several diseases. Probiotics are defined as non-pathogenic live microorganisms that provide beneficial effects to the organism and participate in the prevention and treatment of diseases, which is the reason why it is important to promote interventions that keep intestinal microbiota in eubiosis (microbiota balance). The concentration and balance of the intestinal microbiota depend on several conditions, such as diet, antibiotic consumption, and lifestyle, to mentioned a few. However, interventions with probiotics have shown improvements in both cognitive function and processes that promote neurodegeneration. It is such that the research has been directed on designing strategies that improve not only oral bioavailability but also intestinal adhesion and retention, to clarify the frequency and dosage that should be consumed.},
}

@article {pmid41148458,
year = {2025},
author = {Goel, F and Kumar, D and Singh, P and Rai, SN and Yadav, DK},
title = {Molecular crosstalk between miRNAs and lncRNAs in neurodegenerative disease pathways.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {16},
pmid = {41148458},
issn = {1573-4978},
mesh = {Humans ; *RNA, Long Noncoding/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/therapy ; Gene Expression Regulation ; Animals ; Signal Transduction ; Gene Regulatory Networks ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal degeneration and dysfunction. Of recent interest, a series of studies have been targeting the role of non-coding RNAs, particularly miRNAs and lncRNAs, in regulating gene expression and influencing cellular pathways that may play a critical role in the pathogenesis of these diseases. miRNAs regulate many biological processes by degrading or repressing the translation of target mRNAs, whereas lncRNAs act as scaffolds, sponges, and guides to control gene expression and cellular activities. Both miRNAs and lncRNAs participate in neurodegenerative mechanisms such as protein aggregation, inflammation, oxidative stress, and neuroinflammation. While targeting miRNAs and lncRNAs holds promise for potential therapeutic benefits, problems persist with their efficient delivery, specificity, and off-target effects. New techniques like viral vectors, lipid nanoparticles, and CRISPR-based gene editing will further enhance the development of therapies based on miRNA and lncRNA. Moreover, their interaction with regulatory networks may present new avenues toward understanding disease mechanisms and guiding therapeutic design. This review covers the role of miRNAs and lncRNAs in neurodegenerative disorders, their therapeutic potential, challenges, and future directions in ncRNA-based treatment approaches.},
}

Humans
*RNA, Long Noncoding/genetics/metabolism
*MicroRNAs/genetics/metabolism
*Neurodegenerative Diseases/genetics/metabolism/therapy
Gene Expression Regulation
Animals
Signal Transduction
Gene Regulatory Networks

@article {pmid41147168,
year = {2025},
author = {Hu, D and Li, X and Li, Y and Zhang, Q and Dai, Y and Teng, X and Hou, H and Li, J},
title = {A Drug Screening Targeting Upregulation of Syk Gene Identifies Neochlorogenic Acid and L-Arabinitol Capable of Inducing the M2 Phenotype of Microglia in Alzheimer's Disease.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {},
number = {},
pages = {e202500515},
doi = {10.1002/cbic.202500515},
pmid = {41147168},
issn = {1439-7633},
support = {2023000CA0050//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024100CA0080//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024101RPIA02//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024501QPIC05//Beijing Life Science Academy Initiative Scientific Research Program/ ; },
abstract = {Despite numerous therapeutic attempts of Alzheimer's disease (AD), treatment options remain limited. Targeting microglia (MG) polarization from M1 to M2 is considered a promising approach, yet no drug specifically modulating this transition has been identified. The spleen tyrosine kinase (Syk) has emerged as a potential therapeutic target due to its role in regulating AD risk genes and promoting Amyloid-β (Aβ) clearance. Herein, a microglial reporter gene screening model targeting Syk is developed and two small molecules, neochlorogenic acid (NCGA) and L-arabinitol (L-Ara), that can upregulate Syk gene expression, leading to the activation of MG M2 phenotype, are identified. Furthermore, these compounds markedly enhance the capacity of MG to migrate toward Aβ and phagocytose Aβ. However, when Syk expression is silenced using shRNA, the ability of these small molecules to induce the MG M2 phenotype and promote Aβ phagocytosis by MG is substantially attenuated. These findings offer new insights into AD therapy development.},
}

@article {pmid41145342,
year = {2025},
author = {Dickson, SP and Mallinckrodt, C and Burstein, AH and Nisenbaum, L and Fillit, HM and Zhang, C and Hendrix, SB},
title = {The impact of recent approvals on future alzheimer's disease clinical development: Statistical considerations for combination trials.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100391},
doi = {10.1016/j.tjpad.2025.100391},
pmid = {41145342},
issn = {2426-0266},
abstract = {BACKGROUND: A new era of Alzheimer's disease (AD) research is beginning with multiple approved anti-amyloid monoclonal antibodies (mABs). These drugs are currently not widely used, but may be soon, especially at clinical trial sites. Putative disease-modifying therapies (DMTs) may alter the progression rate, potentially reducing our ability to detect effects on top of mABs. Co-administration of amyloid-targeted agents may diminish benefit (antagonism, due to the overlapping mechanism of action); alternatively, complementary treatment mechanisms may increase benefit (synergy).

METHOD: We consider several clinical trial design scenarios: a 2-arm trial added-on to a mAB, a 2-arm combination compared to double placebo, and a 4-arm full factorial trial. We calculate the required sample sizes for the shortest practical study for secondary prevention (prevention of AD clinical diagnosis in biomarker positive individuals, 2-year study), early AD (18-months), and mild-to-moderate AD (1-year). We consider additivity, antagonism, and synergy.

RESULT: The expected interaction between investigational and mAB treatment can have a large effect on power and study design. Antagonistic treatment effects often require double the sample size of synergistic effects. The 4-arm scenario required ∼10-fold increase compared to a 2-arm combination study.

CONCLUSION: Studies evaluating investigational therapies as add-on to mABs are complex, and their cost will depend on the interaction between treatments. An inescapable fact in add-on trials is the slower progression of the control arm; and it is difficult to further slow already slow progression. Treatments that are likely to work better with amyloid removal will be easier to study due to their complementary MOA. Symptomatic treatments may require fewer additional subjects than disease-modifying treatments since they are less affected by the presence or absence of mABs.},
}

@article {pmid41145339,
year = {2025},
author = {Ballard, C and Sultana, J and Doherty, P and Williams, G and Corbett, A},
title = {Identifying synergistic combinations of repurposed treatments for Alzheimer's Disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100329},
doi = {10.1016/j.tjpad.2025.100329},
pmid = {41145339},
issn = {2426-0266},
abstract = {There is considerable opportunity to fast-track novel treatments for Alzheimer's Disease (AD) through repurposing of existing licensed medications as a way of complementing ongoing drug discovery efforts. Given the complex interplay between AD neuropathological mechanisms, there is also a strong rationale that treatment benefits may be enhanced by examining combinations of treatments to identify potential synergies that would address multiple disease-modifying mechanisms. A Delphi consensus programme combined with a pragmatic analysis of primary care data has identified a series of individual and combined therapies that warrant further investigation in pre-clinical and clinical trials. These include treatments which target well-established neurodegeneration pathways and more explorative agents, including hormonal and anti-infective agents, which align to emerging hypotheses relating to endocrine and immune pathways in AD. Whilst caution is critical when considering combined therapy due to the risks of interaction and polypharmacy, this study provides valuable indications of potential synergistic drug pairs that warrant further investigation.},
}

@article {pmid41145338,
year = {2025},
author = {Cummings, J and Burstein, AH and Fillit, H},
title = {Add-on combination therapy with monoclonal antibodies: Implications for drug development.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100359},
doi = {10.1016/j.tjpad.2025.100359},
pmid = {41145338},
issn = {2426-0266},
abstract = {Three anti-amyloid monoclonal antibodies (MABs) including aducanumab, lecanemab, and donanemab have been approved by the FDA and lecanemab and donanemab are available in the US market and a variety of other national markets. The increasing use of anti-amyloid MABs to treat early AD will require that development of novel agents occur as add-on treatment to MABs. There is limited experience with add-on therapy to anti-amyloid agents. In most cases, it is prudent to initiate novel agents after at least six-months exposure to the MAB at the highest dose. Agents with extensive data on pharmacokinetics and pharmacodynamics and well-known safety may employ alternative approaches. Anti-amyloid MABs have different mechanisms of action, titration, and side effect profiles suggesting that add-on trials include only one type of MAB if possible. Demonstration of clinical benefit with add-on therapy will require showing additional slowing beyond that provided by the anti-amyloid MAB. Anti-amyloid therapies have profound effects on biomarkers including amyloid positron emission tomography and plasma p-tau and plasma GFAP measures. Definition of the biomarker profile of a novel agent prior to initiation of add-on therapies, inclusion of target engagement biomarkers specific to the novel intervention, assessment of biomarkers not known to be affected by anti-amyloid MABs, and interrogation of the magnitude, timing, and trajectory of biomarker change in the add-on context compared to monotherapy with MABs will provide insight into the biological impact of the novel therapy on AD. Patient convenience in terms of formulation and timing of add-on therapies will be important to successful clinical implementation. Add-on therapies are an important step in addressing the complexity of AD and optimizing patient outcomes.},
}

@article {pmid41145337,
year = {2025},
author = {Cummings, JL and Burstein, AH and Fillit, H},
title = {Alzheimer Combination Therapies: Overview and Scenarios.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100328},
doi = {10.1016/j.tjpad.2025.100328},
pmid = {41145337},
issn = {2426-0266},
abstract = {Progress in understanding the complexity of Alzheimer's disease informs the search for combination therapies that can successfully prevent or substantially slow the progression of the disease. Anti-amyloid monoclonal antibodies are the first approved disease targeted therapies; they slow disease progression by approximately 30 %. Building on these agents in add-on therapies is one avenue to designing combination treatments. Development of combination drugs consisting of two or more novel interventions is an alternate pathway for combination treatment development. Combination therapies can involve small molecule drugs, biological agents, devices, stem cells, gene therapies, lifestyle interventions, or cognitive training. Nonclinical assessment of drug combinations may involve animal models or new approach methodologies such as induced pluripotent stem cells or organoids. Phase 1 trials are required to characterize each member of a novel combination. Phase 2 trials may use a 2-by-2 factorial design comparing each drug to placebo and the drug combination. In Phase 3, comparison of the novel combination to standard of care may be sufficient or more complex designs may be required. Targets for combination therapies beyond amyloid-related processes include tau abnormalities, inflammation, neurodegeneration, and co-pathologies such as alpha-synuclein and TDP-43. The choice of combination therapies will depend on the strength of the information regarding the target, biomarkers to guide clinical trials, and a candidate agent with the appropriate mechanism of action. Computational strategies based on network analysis of disease and drugs, validation in non-clinical models, and use of real-world data may facilitate prioritization of candidates for combination treatments.},
}

@article {pmid41144509,
year = {2025},
author = {Morden, NE and Chyn, D and Meara, E},
title = {Falls and Fractures Among Medicare Beneficiaries Concurrently Receiving Anti-Dementia Drugs and Potentially Risky Medications.},
journal = {Medical care},
volume = {},
number = {},
pages = {},
doi = {10.1097/MLR.0000000000002229},
pmid = {41144509},
issn = {1537-1948},
abstract = {BACKGROUND: Patients with Alzheimer disease and related dementias (ADRD) face risks from medications labeled "potentially inappropriate in older adults" (risky); concurrent receipt of anti-dementia drugs may amplify risk. We studied adverse events among older adults concurrently receiving anti-dementia and risky medications.

METHODS: Using 2016-2019 administrative data from a random 40% sample of fee-for-service Medicare beneficiaries receiving anti-dementia medications (acetylcholinesterase inhibitors (AChEI) and/or memantine), we identified days with concurrent receipt of select, risky medications (benzodiazepines, sedative hypnotics, opioids). We measured diagnosed falls, hip fractures, and deaths among person-days with anti-dementia drug receipt comparing person-days with versus without concurrent risky drug receipt. We stratified regression analyses on long-term care (LTC) residence.

RESULTS: We studied 633,528 beneficiaries; 64.3% were women, 33.7% met LTC residence criteria. Mean (SD) age was 80.9 (7.6) years. Each beneficiary contributed a mean (SD) of 551.7 (449.2) anti-dementia drug receipt days. Overall, 4.5% of person-days involved receipt of AChEI plus benzodiazepines; 3.8% involved AChEI plus an opioid. Falls, the most common outcome, affected 22.5% of our beneficiaries. Concurrent receipt of AChEI and opioids was associated with the greatest fall risk increase. Among community-dwelling beneficiaries, AChEI and opioid receipt (vs. AChEI alone) was associated with a hazard ratio for falls of 2.25 (95% CI: 2.19, 2.32); among LTC residents the corresponding hazard ratio was 1.46 (95% CI: 1.42, 1.51).

CONCLUSIONS: Assessment and treatment of symptoms among people with ADRD is complex; concurrent receipt of opioids and dementia medications is uncommon but seems risky. Efforts to eliminate avoidable opioids may decrease adverse events and associated suffering in this population.},
}

@article {pmid41143926,
year = {2025},
author = {Shi, Y and Ma, H and Li, H and Wang, Y and Wang, C and Zhang, N and Luo, G and Wang, Y and Gao, X},
title = {Sennoside A alleviating cognitive impairment in APP/PS1 mice via balancing microbiome metabolism.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389922},
doi = {10.1177/13872877251389922},
pmid = {41143926},
issn = {1875-8908},
abstract = {BackgroundThe progression of Alzheimer's disease (AD) is associated with constipation, potentially mediated by gut microbiota. Laxatives have shown potential in improving the cognitive function of AD, but the specific mechanism remains underexplored. Sennoside A (SA), a well-established laxative, is commonly used for treating constipation.ObjectiveThis work used SA as a probe to explore the therapeutic effects and potential mechanisms of laxatives on AD via the gut-brain axis.MethodsFollowing a two-month treatment, behavioral experiments were used to assess the cognitive function. The central pathologies and neuroinflammation were evaluated by histopathology and ELISA. 16S rRNA sequencing, fecal microbiota transplantation and antibiotic treatment were conducted to verify whether SA exerts anti-AD effects via gut microbiota. Further, non-targeted metabolomics coupled with Spearman correlation analysis was employed to elucidate the underlying mechanisms.ResultsSA significantly countered cognitive dysfunction and central pathological damage in APP/PS1 mice. Besides, SA ameliorated gut dysbiosis and affected the metabolic functions of the flora. Furthermore, the therapeutic effects of SA decrease with the depletion of gut microbes and could be transferred with the microbiota. Intriguingly, amino acid metabolism and aminoacyl-tRNA biosynthesis were the main metabolic pathways regulated by SA, consistent with the predicted functions of gut bacteria. Finally, correlation analysis revealed a strong correlation between gut microbes, fecal metabolites, and cognitive ability affected by SA.ConclusionsThe study investigated the efficacy and mechanisms of laxatives represented by SA for AD from the perspective of the gut-brain axis.},
}

@article {pmid41143875,
year = {2025},
author = {Saak, TM and Tervo, JP and Motter, JN and Overdevest, JB},
title = {Expanding the scope of olfactory evaluation in Alzheimer's disease and related dementias (ADRD): A narrative review of the role for odor memory and recognition in AD/ADRD.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389113},
doi = {10.1177/13872877251389113},
pmid = {41143875},
issn = {1875-8908},
abstract = {Olfactory dysfunction (OD) is a well-characterized feature of Alzheimer's disease (AD) and is often one of the earliest functional biomarkers in the disease course. As such, olfactory evaluation shows promise as an important tool in AD screening and may provide insight into pathologic underpinnings and potential treatment pathways. The National Plan to Address Alzheimer's Disease emphasizes the importance of including Alzheimer's disease related dementias (ADRD) in research efforts, and while olfaction is also associated with ADRD, this association is relatively understudied. Additionally, there have been efforts to expand the evaluation of olfactory function to include assessments beyond key domains, such as odor threshold, odor discrimination, and odor identification, which have been the primary focus of most olfaction research in AD/ADRD. Odor recognition memory assessments have been developed primarily for their utility in identifying and stratifying individuals along the AD continuum, although a wide variety of methods have been reported in the literature. In this narrative review, we provide an overview of odor identification, odor threshold, and odor discrimination in AD/ADRD with a specific focus on providing a centralized guide detailing odor recognition memory methods and their utility in AD/ADRD.},
}

@article {pmid41143243,
year = {2025},
author = {Allué, JA and Sarasa, L and Fandos, N and Gonzalo, R and Sabido-Vera, R and Loscos, J and Romero, J and Sánchez, A and Terencio, J and Matias-Guiu, JA and Piñol-Ripoll, G and Pascual-Lucas, M},
title = {Clinical validation of a plasma-based antibody-free LC-MS method for identifying CSF amyloid positivity in mild cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1681516},
pmid = {41143243},
issn = {1663-4365},
abstract = {BACKGROUND: The recent approval of monoclonal antibodies for the treatment of Alzheimer's disease (AD) in several countries has accelerated the need for affordable, simple and scalable methods to identify patients who are eligible for treatment with the new disease-modifying therapies (DMT). Blood-based biomarkers offer less invasive alternatives to established gold standards. We have clinically validated a predictive model combining plasma Aβ42/Aβ40, apolipoprotein E (APOE) genotype and age, in two independent real-world cohorts to identify brain amyloid deposition.

METHODS: We conducted a clinical validation study involving 450 patients with mild cognitive impairment (MCI) from two real-world cohorts (HCSC, Madrid, Spain and HUSM, Lleida, Spain). Plasma Aβ42/Aβ40 was measured by ABtest-MS, an antibody-free liquid chromatography-mass spectrometry method. CSF Aβ42/Aβ40 and p-tau181/Aβ42 (gold standards) were quantified with the Lumipulse[®] platform. The model was trained in the HCSC cohort and validated in the HUSM cohort. Finally, an overall analysis in the combined population was performed. A dual cutoff approach was used to classify the patients as positive or negative. Statistical analysis included bootstrap resampling and model calibration.

RESULTS: In the HCSC, HUSM, external validation and combined analysis, AUCs were 0.89 (95% confidence intervals-CI: 0.84-0.93), 0.88 (0.84-0.93), 0.88 (0.83-0.92) and 0.88 (0.84-0.91), with corresponding accuracies of 82.3, 81.6, 82.3, and 81.1%, respectively. After the combined analysis, positive and negative predictive values (PPV and NPV) were established at 87.5%, resulting in cutoff values of 0.30 and 0.67 for the likelihood of amyloid negativity and positivity, respectively, for a prevalence of 62%. Probability values lower than 0.30 indicate low probability of brain amyloid deposition, while values greater than 0.67 indicate high probability. Less than 28% of the participants fell into the intermediate zone. Additional cutoffs were derived for different prevalence values. Predictive model calibration showed excellent agreement with observed data, confirming accurate predictions (slope = 0.98, intercept = -0.01).

CONCLUSION: This predictive model has demonstrated high accuracy for the identification of brain amyloid deposition in patients with MCI. Derived cutoffs enabled over 70% reduction in invasive testing, supporting efficient and cost-effective identification of candidates for DMTs.},
}

@article {pmid41141907,
year = {2025},
author = {Blazquez-Folch, J and Limones Andrade, M and Calm, B and Auñón García, JM and Alegret, M and Muñoz, N and Cano, A and Fernández, V and García-Gutiérrez, F and De Rojas, I and García-González, P and Olivé, C and Puerta, R and Capdevila-Bayo, M and Muñoz-Morales, Á and Bayón-Buján, P and Miguel, A and Montrreal, L and Espinosa, A and Sanz-Cartagena, P and Rosende-Roca, M and Zaldua, C and Gabirondo, P and Cantero-Fortiz, Y and Gurruchaga, MJ and Tarraga, L and Boada, M and Ruiz, A and Marquié, M and Valero, S},
title = {Federated learning for cognitive impairment detection using speech data.},
journal = {Frontiers in artificial intelligence},
volume = {8},
number = {},
pages = {1662859},
pmid = {41141907},
issn = {2624-8212},
abstract = {INTRODUCTION: In Alzheimer's disease (AD) research, clinical, neuroimaging, genetic, and biomarker data are vital for advancing its understanding and treatment. However, privacy concerns and limited datasets complicate data sharing. Federated learning (FL) offers a solution by enabling collaborative research while preserving data privacy.

METHODS: This study analyzed data from patients assessed at the Memory Unit of the Ace Alzheimer Center Barcelona who completed a standardized digital speech protocol. Acoustic features extracted from these recordings were used to distinguish between cognitively unimpaired (CU) and cognitively impaired (CI) individuals. The aim was to evaluate how data heterogeneity impacted the FL model performance across three scenarios: (1) equal contributions and class ratios, (2) unequal contributions, and (3) imbalanced class ratios. In each scenario, the performance of local models trained using an MLP feed-forward neural network on institutional data was analyzed and compared to a global model created by aggregating these local models using Federated Averaging (FedAvg) and Iterative Data Aggregation (IDA).

RESULTS: The cohort included 2,239 participants: 221 CU individuals (mean age 66.8, 64.7% female) and 2,018 CI subjects, comprising 1,219 with mild cognitive impairment (mean age 74.3, 61.9% female) and 799 with mild AD dementia (mean age 80.8, 64.8% female). In scenarios 1 and 3, FL provided modest gains in accuracy and AUC. In scenario 2, FL markedly improved performance for the smaller dataset (balanced accuracy rising from 0.51 to 0.80) while preserving 0.86 accuracy in the larger dataset, highlighting scalability across heterogeneous conditions.

CONCLUSION: These findings demonstrate the potential of FL to enable collaborative modeling of speech-based biomarkers for cognitive impairment detection, even under conditions of data imbalance and institutional disparity. This work highlights FL as a scalable and privacy-preserving approach for advancing digital health research in neurodegenerative diseases.},
}

@article {pmid41141199,
year = {2025},
author = {Sorod, P and Chen, GI},
title = {Hearing All About Donepezil: Its Role in the Field of Auditory Processing.},
journal = {Cureus},
volume = {17},
number = {9},
pages = {e93143},
pmid = {41141199},
issn = {2168-8184},
abstract = {Donepezil is a central-acting acetylcholinesterase inhibitor aimed at increasing acetylcholine availability at the neuron synapses to enhance cholinergic transmission. It is often used to assist with cognitive function and is well-known as the first-line treatment for mild to severe dementia of several etiologies. However, its mechanism of action within "top-down" and "bottom-up" neurological pathways continues to be explored. This case reports on a 93-year-old woman in an ambulatory geriatrics clinic with moderate-to-severe dementia. Her significant history of hearing loss with auditory hallucination impressively responded to the initiation of donepezil. There may be potential benefits of donepezil within the peripheral pathways of neuro-cortical reorganization in the field of hearing loss and auditory processing.},
}

@article {pmid41140221,
year = {2025},
author = {Mastrostefano, A and Alborghetti, M and Tiso, D and Davinelli, S and Medoro, A and Scapagnini, G},
title = {Pleiotropic Actions of Gastrodia Elata Glucosides in the Treatment of Painful Neuropathies and CNS Disorders: Focus on Mitochondrial Dysfunction and Modulation of Ion Channels.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X402568251002112117},
pmid = {41140221},
issn = {1875-6190},
abstract = {Glycosides contained in Gastrodia elata have consistently shown neuroprotective and antiinflammatory activity in preclinical models of neurological disorders, including peripheral neuropathies, cerebrovascular disorders, and chronic neurodegenerative disorders. In a commercial product used in Italy, gastrodin has replaced α-lipoic, the use of which is now limited by unexpected adverse effects, such as severe hypoglycemia. The clinical efficacy of gastrodin in traditional Chinese medicine has been ascribed to a plethora of mechanisms, which involve the modulation of intracellular signaling pathways and membrane ion channels. Moving from the pathophysiology of diabetic neuropathy, Alzheimer's disease, and Parkinson's disease, we now focus on what we consider a key mechanism in the action of gastrodin, i.e., the regulation of mitochondrial quality control. Gastrodin is able to enhance mitochondrial fusion and biogenesis, as shown by the induction of specific biochemical markers, such as mitofusins and mitochondrial transcription factors. This supports mitochondrial health, preventing the loss of energy production and formation of reactive oxygen species associated with disorders of the central and peripheral nervous system. In addition, gastrodin physically interacts with, and restrains the expression and activity of, voltage-sensitive ion channels and acid-sensing ion channels, which play a central role in pain transmission and nociceptive sensitization. Thus, gastrodin and other constituents of Gastrodia elata show promising potential to support first-line treatments, based on preclinical evidence in models of neurological disease.},
}

@article {pmid41140219,
year = {2025},
author = {Devi, S and Singh, AP},
title = {Novel Therapeutic Approaches to Neuroinflammation in Neurodegenerative Disorders: Aptamers as Central Nervous System Agents.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249392444251002135338},
pmid = {41140219},
issn = {1875-6166},
abstract = {INTRODUCTION: Neurodegenerative disorders (NDDs) like Alzheimer's, Parkinson's, and multiple sclerosis all begin with neuroinflammation. Neuroinflammation targeting has recently gained attention as a potential approach to treating several diseases affecting the central nervous system. The objective of this review is to explore the potential of aptamers as innovative therapeutic agents for targeting neuroinflammation in neurodegenerative disorders, offering a novel approach to CNS treatment.

METHODS: The use of aptamers, which are single-stranded nucleic acids, in diagnostic and therapeutic contexts may one day help overcome these obstacles. Myotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders are linked to neuroinflammation. Important regulators of CNS inflammatory responses include microglia and astrocytes.

RESULTS: Neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) and neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes) activation of microglia and astrocytes, respectively, is a diverse and complex process. There may be a lack of reflection of the diverse morphologies of microglia and astrocytes in this binary categorisation. In addition to the complexity of the relationships between these activated glial cells, the phenotypic distribution can vary as neurodegenerative illnesses progress.

DISCUSSION: To create effective treatments for neurodegenerative illnesses, a deeper knowledge of microglia and astrocyte functions is required. Drug efficacy, safety concerns, and pharmacokinetics are only a few of the topics covered, along with the enormous possibilities and enormous hurdles of employing aptamers as therapeutic agents.

CONCLUSION: This review highlights aptamers as a promising genetic tool for treating neuroinflammation and neurodegenerative diseases through targeted delivery to the central nervous system.},
}

@article {pmid41140213,
year = {2025},
author = {Zhao, R and Che, M and Cui, Y and Peng, J and Chen, M},
title = {The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050407276251014113234},
pmid = {41140213},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is inadequately comprehended, with hypotheses implicating amyloid-β, tau pathology, mitochondrial dysfunction, and epigenetic factors. Recent research underscores the significance of lipoproteins and the gut microbiota in the etiology of AD. Apolipoprotein E (ApoE), particularly the E4 subtype, emerges as a key genetic risk factor, influencing oxidative stress, synaptic defects, glucose metabolism, and amyloid-β clearance. Lipoprotein receptors, such as LRP-1, also influence the integrity of the blood-brain barrier, indicating potential for therapeutic applications. Novel therapies targeting lipoproteins, such as ALZ-801 and IDOL inhibitors, show promise in preclinical and clinical trials. Concurrently, the gut microbiome's impact on AD is increasingly recognized. Dysbiosis correlates with inflammation, mitochondrial oxidative stress, impaired autophagy, and neurotransmitter imbalances. Gut-derived metabolites, including phenylalanine and isoleucine, promote Th1 cell activation and microglial dysfunction, exacerbating AD pathology. Interventions, like probiotics, GV-971, and polyphenols, demonstrate efficacy in restoring microbial balance and mitigating cognitive decline. Crucially, bidirectional interactions between lipoproteins and the gut microbiome are implicated in AD. ApoE genotypes influence gut microbial composition, while microbiota- derived short-chain fatty acids and endotoxins modulate lipid metabolism and neuroinflammation. These interactions, mediated via the gut-brain axis, highlight novel therapeutic avenues. Current FDA-approved AD drugs face limitations in efficacy and side effects, underscoring the need for innovative strategies targeting lipoprotein-gut microbiome crosstalk. Integrating insights into lipoprotein biology and gut microbiota dynamics may offer transformative potential for AD treatment, emphasizing combinatorial approaches to modulate these interconnected pathways. Further research is warranted to elucidate mechanistic links and translate preclinical findings into clinical applications.},
}

@article {pmid41140062,
year = {2025},
author = {Abdel-Lah, ES and Hamad, N and Taha, AF and Mohamed, WH and Fawy, MA and Attaai, AH and Abbas, FYA and Sherkawy, HS and Abdelwarith, A and Gamea, MG},
title = {Neuroprotective Effect of Empagliflozin/Rivastigmine in Alzheimer's Disease Rat Model: Optimization of Multifaceted Mechanism of Action.},
journal = {Drug development research},
volume = {86},
number = {7},
pages = {e70180},
doi = {10.1002/ddr.70180},
pmid = {41140062},
issn = {1098-2299},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Animals ; *Rivastigmine/pharmacology/administration & dosage ; *Glucosides/pharmacology/administration & dosage/therapeutic use ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Male ; *Benzhydryl Compounds/pharmacology/administration & dosage/therapeutic use ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Acetylcholinesterase/metabolism ; Glucose/metabolism ; Brain/drug effects/pathology/metabolism ; Rats, Wistar ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; tau Proteins/metabolism ; Drug Therapy, Combination ; Lipid Peroxidation/drug effects ; },
abstract = {This study assessed the neuroprotective potential of empagliflozin (EMPA) as antidiabetic drug on glucose metabolism, comparing it to rivastigmine (RIVA) as standard treatment for Alzheimer's disease (AD), and their combination. Male rats were sorted into five groups. Group I served as the control, while groups II, III, IV, and V received the scopolamine plus heavy metal mixture for AD induction. Groups III and IV were administered RIVA and EMPA, respectively, and group V received both treatments. Cognitive function was evaluated behaviorally. Subsequently, glucose levels, acetylcholinesterase, oxidative stress, and inflammatory markers were assessed. Alongside the brain histopathological changes, the expression of phosphorylated tau protein was assessed. Moreover, glycolytic enzymes and glucose transporters were assessed using PCR analysis. The findings were attributed to a notable suppressive impact of EMPA on lipid peroxidation, acetylcholinesterase, glucose levels, phosphorylated tau protein, pro-inflammatory cytokines, and neuropathological changes, while enhancing antioxidant and interleukin-10 levels. It also improves glucose metabolism. The findings suggest that EMPA may be a viable candidate for future therapeutic exploration in AD, which has a multifaceted mechanism of action encompassing anti-neuroinflammation, antioxidant stress, and enhanced glucose metabolism, as well as decreased acetylcholinesterase activity and phosphorylated tau protein levels. Interestingly, combined treatment showed a superior effect than EMPA alone.},
}

Animals
*Rivastigmine/pharmacology/administration & dosage
*Glucosides/pharmacology/administration & dosage/therapeutic use
*Neuroprotective Agents/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
Male
*Benzhydryl Compounds/pharmacology/administration & dosage/therapeutic use
Rats
Disease Models, Animal
Oxidative Stress/drug effects
Acetylcholinesterase/metabolism
Glucose/metabolism
Brain/drug effects/pathology/metabolism
Rats, Wistar
Sodium-Glucose Transporter 2 Inhibitors/pharmacology
tau Proteins/metabolism
Drug Therapy, Combination
Lipid Peroxidation/drug effects

@article {pmid41139687,
year = {2025},
author = {Li, X and Singh, S and DeVries, A and Gurwitz, JH},
title = {Lecanemab Therapy Use Patterns for Alzheimer's Disease Among Early Initiators in a Large National Health Plan.},
journal = {Journal of the American Geriatrics Society},
volume = {73},
number = {10},
pages = {3203-3207},
doi = {10.1111/jgs.70010},
pmid = {41139687},
issn = {1532-5415},
support = {3R33AG057806-07S1/AG/NIA NIH HHS/United States ; K01AG073651/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Aged ; Male ; United States ; Medicare Part C/statistics & numerical data ; Magnetic Resonance Imaging ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; Aged, 80 and over ; },
abstract = {BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, has been approved for treatment of early Alzheimer's disease. However, real-world data remain limited regarding use.

METHODS: Using data from a large national health plan with primarily Medicare Advantage enrollees, we characterized demographic and clinical characteristics in the 6 months preceding the initial infusion among individuals who initiated lecanemab between 1/1/2023 and 06/30/2024. We also characterized the patterns of infusions and the timing of MRIs for safety monitoring following the initial infusion among initiators who had ≥ 3 months of follow-up. We further assessed trends in lecanemab use between 1/1/2023 and 12/31/2024.

RESULTS: Of the 195 lecanemab initiators, the average age was 74.6 (SD = 5.5) years, 62.1% were female, 87.7% were White, 4.1% were Black, 1.5% were Hispanic, and 98.5% were on a Medicare Advantage plan. Almost all initiators resided in nonrural areas (96.4%); 2.6% used anticoagulants, and 1.5% used antiplatelets. Among the 119 initiators who had ≥ 3 months of follow-up, 40 (33.6%) received 7 total infusions, the expected number of infusions based on the recommended schedule of every 2 weeks. From the initial infusion, the average number of days to the first MRI was 47.1 (SD = 15.8), and to the second MRI scan was 73.4 (SD = 12.0) days, consistent with the recommended schedule. During 2023-2024, there were 526 patients who had ever received lecanemab. The increase in new initiators was modest over 2024, with only 43 more initiators during the final (n = 137) versus the first quarter (n = 94) of 2024.

CONCLUSIONS: This study demonstrated slow uptake of lecanemab among Medicare Advantage beneficiaries. Adherence to the ideal treatment schedule was less than recommended. Early lecanemab users were not representative of the population likely eligible for treatment nationally. Further research is warranted to track longer-term trends in utilization, as well as reasons for treatment interruption or discontinuation in real-world populations.},
}

Humans
*Alzheimer Disease/drug therapy
Female
Aged
Male
United States
Medicare Part C/statistics & numerical data
Magnetic Resonance Imaging
*Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage
Aged, 80 and over

@article {pmid41139428,
year = {2025},
author = {Justo-Henriques, SI and Lemos, R and Rahmatpour, P and Silva, RCG and Carvalho, JO and Ribeiro, O},
title = {Effectiveness of Individual Cognitive Stimulation on Cognition in Mild Alzheimer's Disease: A Multicenter RCT.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {25},
number = {6},
pages = {e70109},
doi = {10.1111/psyg.70109},
pmid = {41139428},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; Aged ; *Executive Function/physiology ; Neuropsychological Tests ; Treatment Outcome ; *Cognition/physiology ; Aged, 80 and over ; *Cognitive Behavioral Therapy/methods ; Memory ; Portugal ; *Cognitive Dysfunction/therapy ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is characterised by impairments across several neurocognitive domains, including memory and executive function. The study explored the effectiveness of a 3-month individual Cognitive Stimulation (iCS) program in older adults with mild AD.

METHODS: A multicenter randomised controlled trial was conducted with 62 Portuguese older adults with mild AD. Participants were randomly assigned to either iCS (n = 33; 53%) or treatment as usual (TAU, n = 29; 47%). Cognitive outcomes were assessed at baseline, post-intervention, and 12-week follow-up using standardised tests for global cognition, memory and executive function.

RESULTS: The iCS group showed a significant improvement in memory and executive function compared to the TAU group. The analysis of subscales revealed significant improvements in encoding and semantic memory (Memory Alteration Test) and free delayed recall (Free and Cued Selective Reminding Test). Adherence and engagement with the intervention were high.

CONCLUSIONS: A 3-month iCS program showed preliminary benefits in specific cognitive domains (memory and executive function) in older adults with mild AD, warranting further research with larger samples and longer follow-up.

TRAIL REGISTRATION: Clinicaltrials.gov ID: NCT05433493; Effect of Individual Cognitive Stimulation on Memory and Executive Function in Older Adults With Alzheimer's Disease.},
}

Humans
*Alzheimer Disease/therapy/psychology
Female
Male
Aged
*Executive Function/physiology
Neuropsychological Tests
Treatment Outcome
*Cognition/physiology
Aged, 80 and over
*Cognitive Behavioral Therapy/methods
Memory
Portugal
*Cognitive Dysfunction/therapy

@article {pmid41139132,
year = {2025},
author = {Sonwani, A and Pathak, A and Jain, K},
title = {Development and characterization of multifunctional dendrimeric nanoconjugates for delivery of rutin: in vitro characterization for potential neuroprotective application.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17435889.2025.2576463},
pmid = {41139132},
issn = {1748-6963},
abstract = {AIM: In the present research work, multifunctional dendrimeric nanoconjugates were developed, where poly(amidoamine) dendrimer generation 4.0 (G4.0) was conjugated with folic acid and N-acetyl cysteine simultaneously to deliver rutin for potential neuroprotective applications.

METHODS: G4.0 was functionalized with folic acid and N-acetyl cysteine by carbodiimide coupling chemistry, and the conjugation was confirmed using [1]H NMR and FTIR spectroscopy. Further, rutin was incorporated within the conjugate, and the rutin-loaded dendrimeric conjugate was evaluated for size, drug release, cytotoxicity, cellular uptake, and antioxidant activity.

RESULTS: The results of FTIR and [1]H NMR confirmed the conjugation of folic acid and N-acetyl cysteine over the dendrimeric surface. The particle size of NAC-FA-G4.0 was 163.4 ± 16.63 nm, which was increased to 229.76 ± 14.05 nm following the rutin incorporation. The in vitro drug release study showed an initial burst release of rutin, i.e. 44.27 ± 6.4% from dendrimeric conjugate within 4 h, followed by sustained release up to 72 h. The safety and biocompatibility of the developed nanoconjugate were confirmed by the hemolytic toxicity and cytotoxicity studies.

CONCLUSION: The developed rutin-loaded dendrimeric conjugate showed improved antioxidant activity and acetylcholinesterase inhibition, suggesting promising neuroprotection properties and hence may be further explored for the treatment of neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41139043,
year = {2025},
author = {Yu, C and Liu, L and Lu, Z and Chen, M and Yang, N and Li, Z and Bai, L and Li, C and Zhou, X},
title = {A new approach for treating AD: Guifu Dihuang Pills improves brain insulin resistance by promoting NrCAM to activate the EGFR/PI3K/Akt signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120642},
doi = {10.1016/j.jep.2025.120642},
pmid = {41139043},
issn = {1872-7573},
abstract = {Guifu Dihuang Pills (GFDHP), a classical Chinese herbal formula originally recorded in the Synopsis of the Golden Chamber (Jingui Yaolüe), significantly ameliorate cognitive dysfunction in patients with Alzheimer's disease (AD). However, the precise molecular mechanisms underlying its therapeutic effects, particularly those involving the regulation of cerebral insulin resistance (IR), are not yet fully elucidated.

AIM OF THE STUDY: This study systematically investigated the neuroprotective mechanism of the traditional Chinese medicine (TCM) compound GFDHP in alleviating AD by integrating RNA-seq transcriptomics, surface plasmon resonance (SPR) analysis, and bioinformatic analysis. The aim was to clarify its key targets and signaling pathways involved in the modulation of cerebral IR by in vitro and in vivo experiments.

METHODS: The chemical components of GFDHP were characterized using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). An AD model with cerebral IR was established by an intracerebroventricular streptozotocin (ICV-STZ) injection. Cognitive function was assessed using the Morris water maze (MWM) test, while hippocampal damage was evaluated by histological staining. The insulin level in hippocampal tissues was quantified using enzyme-linked immunosorbent assay (ELISA). AD-related proteins were analyzed using immunohistochemistry and western blot. Integrated transcriptome sequencing, AlphaFold3 prediction, and SPR analysis confirmed the interaction between neuronal cell adhesion molecule (NrCAM) and epidermal growth factor receptor (EGFR). In vitro experiments were performed using HT22 cells treated with dexamethasone (DXM) to induce an IR model, followed by evaluation of IR and AD-related markers. Lentivirus-mediated shRNA knockdown of NrCAM was performed to systematically examine its regulatory effect on the EGFR/PI3K/Akt signaling pathway and GFDHP's therapeutic intervention.

RESULTS: GFDHP significantly attenuated ICV-STZ-induced IR and AD-related neuropathological alterations. SPR analysis further revealed that NrCAM mediated the neuroprotective effect through the specific binding to EGFR, thereby activating the downstream PI3K/Akt signaling cascade. NrCAM silencing not only exacerbated both IR and AD pathology but also suppressed the EGFR/PI3K/Akt pathway and reduced the therapeutic effect of GFDHP.

CONCLUSIONS: This study demonstrated that GFDHP alleviated IR by upregulating NrCAM expression and subsequently activating the EGFR/PI3K/Akt signaling pathway, thereby ameliorating AD. This is the first report identifying NrCAM as the key molecular target mediating the neuroprotective effect of this herbal formulation, providing a novel therapeutic strategy for AD treatment.},
}

@article {pmid41138654,
year = {2025},
author = {Ha, TY and Kim, Y and Lim, SM and Hong, Y and Chang, KA},
title = {GPR40 agonist ameliorates neurodegeneration by regulating mitochondria dysfunction and NLRP3 inflammasome in Alzheimer's disease animal models.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {192},
number = {},
pages = {118678},
doi = {10.1016/j.biopha.2025.118678},
pmid = {41138654},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction and chronic neuroinflammation. G-protein coupled receptor 40 (GPR40), primarily known for its role in metabolic regulation, has recently emerged as a modulator of neuronal activity and inflammatory signaling. In this study, we investigated the therapeutic potential of the selective GPR40 agonist TUG469 in both in vitro and in vivo models of AD. Treatment with amyloid-β oligomers (AβO) induced mitochondrial dysfunction in primary hippocampal neurons, as evidenced by disrupted mitochondrial morphology and membrane potential. TUG469 treatment restored mitochondrial integrity and membrane potential. Moreover, TUG469 significantly reduced AβO-induced reactive oxygen species (ROS) production. In the 5xFAD mouse model of AD, TUG469 administration improved cognitive performance and reduced Aβ plaque burden. Furthermore, TUG469 rescued impaired autophagy flux, as demonstrated by the regulation of LC3, p62, and LAMP1 expression, and attenuated neuroinflammatory responses by inhibiting NLRP3 inflammasome activation and modulating microglial reactivity. These findings indicate that GPR40 activation mitigates mitochondrial dysfunction and neuroinflammation, thereby alleviating AD-related pathology. Our results highlight the therapeutic potential of TUG469 as a multi-target modulator for AD.},
}

@article {pmid41141948,
year = {2023},
author = {Sarko, L and Saha, K},
title = {Harnessing chimeric antigen receptor (CAR)-T cells as a potential treatment for Alzheimer's disease.},
journal = {Cell & gene therapy insights},
volume = {9},
number = {7},
pages = {1003-1010},
pmid = {41141948},
issn = {2059-7800},
abstract = {Alzheimer's disease (AD) significantly burdens global healthcare systems given limited treatment options to delay or stop disease progression. Chimeric antigen receptor (CAR) T cell therapy, an immunotherapeutic approach that has produced remarkably effective responses in cancer, offers a potential avenue for the treatment of AD. Here, we discuss three significant challenges of adapting CAR-T cell therapy for AD: (i) identifying a suitable antigen target; (ii) limited permeability of the blood-brain barrier; and (iii) long-term persistence and durability of manufactured CAR-T cell products. Potential strategies to overcome these hurdles provide an attractive opportunity to revolutionize the treatment for AD and potentially other neurodegenerative disorders.},
}

@article {pmid41138336,
year = {2025},
author = {Waheed, R and Mostafa, Z and Emad, M and Darwish, SS and Purgatorio, R and Miniero, DV and De Palma, A and Cheng, TP and Wang, TY and Chen, YC and El Kerdawy, AM and Gabr, M and Catto, M and Abadi, AH and Hwang, TL and Abdel-Halim, M},
title = {Revisiting COX-2 inhibitors for Alzheimer's disease as multitargeted ligands: Development of 4-hydrazono-pyrazolidinediones with tuned COX selectivity profile and improved cellular potency.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 1},
pages = {118261},
doi = {10.1016/j.ejmech.2025.118261},
pmid = {41138336},
issn = {1768-3254},
abstract = {Herein, we expand on our previously synthesized 4-hydrazono-pyrazolidinedione COX-2 inhibitors as multitargeted agents for Alzheimer's disease (AD). Structural modifications of the 4-phenylhydrazono group led to the identification of several highly potent COX-2 inhibitors, with compound 3 exhibiting the strongest COX-2 inhibition (IC50 = 0.07 μM), with a balanced COX-2/COX-1 profile, suggesting lower cardiovascular risk. Compounds 2 and 9 showed high potency and selectivity shift toward COX-1 and displayed strong antiplatelet activity. Several derivatives showed 4-7 times improved submicromolar cellular potency, significantly inhibiting PGE2 release in LPS-stimulated THP-1 cells. Compounds 2, 3, 7, and 9 maintained the multitarget profile and inhibited Aβ and tau aggregation. Compounds 2, 3, and 7 protected against Amyloid-beta (Aβ)- and H2O2-induced cytotoxicity, confirming their neuroprotective activity with high potential for BBB permeability demonstrated via PAMPA and MDCK-MDR1 assays. These results support the potential of multitargeted COX-2 inhibitors as AD therapeutics and suggest a re-evaluation of their role in neurodegenerative disease treatment.},
}

@article {pmid41138018,
year = {2025},
author = {Hu, L and Qi, L and Lin, Z and Zhu, J and Zhang, M},
title = {Research progress of single cell RNA sequencing in nervous system.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {9},
pmid = {41138018},
issn = {1573-4978},
support = {82271747//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Single-Cell Analysis/methods ; *Sequence Analysis, RNA/methods ; *Nervous System/metabolism ; Transcriptome/genetics ; *Nervous System Diseases/genetics ; Animals ; Gene Expression Profiling/methods ; },
abstract = {Single-cell RNA sequencing (scRNA-seq) and its integration with multi-omics technologies such as epigenomics and spatial transcriptomics are revolutionizing our traditional understanding of cellular heterogeneity and the microenvironment in the nervous system. While technical reviews abound, translating multi-omics data into biological and clinical insights remains a challenge. This review comprehensively outlines the latest advancements in scRNA-seq technology and its integration with multi-omics approaches and artificial intelligence. We systematically summarize its applications across neuroscience, from unraveling neurodevelopment and evolution to deciphering the mechanisms of neurological diseases such as Alzheimer's disease, Parkinson's disease, and gliomas. By deeply resolving cell-specific expression differences in neurological disorders, scRNA-seq has enabled the discovery of novel cell subtypes and revealed intercellular regulatory mechanisms, thereby facilitating the deconstruction of disease pathogenesis and the identification of new potential therapeutic targets. Furthermore, this technology has demonstrated significant value in drug screening, efficacy evaluation, and the development of novel treatment strategies. However, scRNA-seq still faces multiple technical limitations. Future efforts should focus on reducing its application costs, addressing clinical ethical concerns, and progressively advancing the clinical translation of scRNA-seq technology.},
}

Humans
*Single-Cell Analysis/methods
*Sequence Analysis, RNA/methods
*Nervous System/metabolism
Transcriptome/genetics
*Nervous System Diseases/genetics
Animals
Gene Expression Profiling/methods

@article {pmid41137894,
year = {2025},
author = {Gu, X and Yu, SP and Jiang, MQ and Zhong, W and Sastry, A and Wei, L},
title = {Preventive Memantine Treatment at the Preclinical Stage in the Alzheimer's Disease Model of the 5xFAD Mouse.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41137894},
issn = {1995-8218},
abstract = {Neuronal and NMDA receptor (NMDAR) hyperactivities are common pathophysiology in Alzheimer's disease (AD). We recently identified that the deficiency of NMDAR regulatory subunit GluN3A (NR3A) cultivated early psychological and olfactory symptoms, followed by cognitive decline and deferred endogenous amyloid/tau pathologies. NMDAR antagonist memantine (MEM) prevented AD-like progression in GluN3A knockout (KO) mice. We tested the hypothesis that AD development of the 5xFAD mouse can be antagonized by the preemptive MEM treatment. MEM (10 or 20 mg/kg per day in drinking water for 3 months) was started in wild-type (WT) and 5xFAD mice at 3 months old. In this preclinical stage, the 5xFAD mouse displayed psychological and olfactory symptoms, yet exhibited no significant cognitive deficits or Aβ42 deposition. The MEM treatment antagonized early symptoms, abated cognitive decline, and amyloid/tau pathology. Early and persistent maintenance of normal neuronal/NMDAR activities in individuals carrying AD risk factors should be considered as a preventive and a possible disease-modifying therapy.},
}

@article {pmid41137616,
year = {2025},
author = {Chan, D and de Weck, G and Jackson, BL and Suk, HJ and Milman, NP and Kitchener, E and Avalos, VSF and Quay, MJ and Aoki, K and Ruiz, E and Becker, A and Zheng, M and Philips, R and Firenze, R and Geigenmüller, U and Hammerschlag, B and Arnold, S and Kivisäkk, P and Brickhouse, M and Touroutoglou, A and Brown, EN and Boyden, ES and Dickerson, BC and Klerman, EB and Tsai, LH},
title = {Gamma sensory stimulation in mild Alzheimer's dementia: An open-label extension study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70792},
doi = {10.1002/alz.70792},
pmid = {41137616},
issn = {1552-5279},
support = {//Freedom Together Foundation/ ; //Robert A. and Renee E. Belfer Family Foundation/ ; //Eleanor Schwartz Charitable Foundation/ ; //The Dolby Family/ ; //Che King Leo/ ; //Amy Wong and Calvin Chin/ ; //Kathleen and Miguel Octavio/ ; //the Degroof-VM Foundation/ ; //Halis Family Foundation/ ; //Chijen Lee/ ; //Eduardo Eurnekian/ ; //Larry and Debora Hilibrand/ ; //Gary Hua and Li Chen/ ; //Ko Han Family/ ; //Lester Gimpelson/ ; //David B. Emmes/ ; //Joseph P. DiSabato and Nancy E. Sakamoto/ ; //Donald A. and Glenda G. Mattes/ ; //Alan and Susan Patricof/ ; //Carol and Gene Ludwig Family Foundation/ ; //Alex Hu and Anne Gao/ ; //Elizabeth K. and Russell L. Siegelman/ ; //Marc Haas Foundation/ ; //Dave and Mary Wargo/ ; //James D. Cook, and the Nobert H. Hardner Foundation/ ; UDIW8172//NIH Loan Repayment Program/ ; 15367//Doris Duke Clinical Scientist Development Award/ ; //Picower Clinical Fellowship/ ; UL1 TR002541/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging ; Female ; Aged ; Electroencephalography ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Male ; Biomarkers/blood ; Brain/diagnostic imaging/physiopathology ; Aged, 80 and over ; tau Proteins/blood ; *Acoustic Stimulation/methods ; *Photic Stimulation/methods ; Cognition/physiology ; Mental Status and Dementia Tests ; },
abstract = {INTRODUCTION: We evaluated the long-term effects of daily 40 Hz (gamma frequency) audiovisual stimulation on cognition and biomarkers in five patients with mild Alzheimer's disease (AD).

METHODS: Over 2 years, patients received 1-h daily stimulation. Electroencephalography (EEG) was used to assess neural entrainment; magnetic resonance imaging (MRI) measured brain volumes; actigraphy monitored activity patterns; neuropsychological tests evaluated cognition; and S-PLEX assay measured plasma pTau217.

RESULTS: No adverse events occurred over the study period. Three female patients with late-onset AD (LOAD) retained strong EEG entrainment and showed less decline in Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Functional Assessment Scale (FAS) scores compared to matched controls from National Alzheimer's Coordinating Center (NACC), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). Plasma samples were available for only two of five participants - both with LOAD - and both showed pTau217 reductions of 47% and 19%.

DISCUSSION: These findings suggest that long-term 40 Hz audiovisual stimulation is safe, feasible, and may offer cognitive and biomarker benefits in some individuals with mild AD, supporting further investigation.

ClinicalTrials.gov (NCT04055376).

HIGHLIGHTS: Five mild Alzheimer's disease (AD) patients safely used daily 40 Hz audiovisual stimulation for 2 years. Late-onset AD (LOAD) patients showed increased 40 Hz electroencephalography (EEG) power and improved cognitive scores. National Alzheimer's Coordinating Center (NACC) data enhanced early-phase analysis and support precision medicine in AD studies. Plasma pTau217 declined in 2 LOAD patients after 2 years of daily use. This small pilot is the first to link long-term 40 Hz therapy to AD biomarker change.},
}

Humans
*Alzheimer Disease/therapy/physiopathology/diagnostic imaging
Female
Aged
Electroencephalography
Magnetic Resonance Imaging
Neuropsychological Tests
Male
Biomarkers/blood
Brain/diagnostic imaging/physiopathology
Aged, 80 and over
tau Proteins/blood
*Acoustic Stimulation/methods
*Photic Stimulation/methods
Cognition/physiology
Mental Status and Dementia Tests

@article {pmid41137085,
year = {2025},
author = {Zhang, W and Song, J and Zhong, F and Yu, W and Qin, Z and Yang, Z and Liu, J and Wang, X and Chen, L and Lü, W and Xing, D and Liu, J and Huang, C and Wu, J and Liu, X and Yu, W and Lü, Y},
title = {Computerized cognitive training enhances cognitive function in Alzheimer's disease by downregulating Ruminococcus-TMAO pathway.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1173},
pmid = {41137085},
issn = {1479-5876},
support = {2022YSZX-JSX0002CSTB//grants from Innovation Programs Led by the Academicians in Chongqing under Project/ ; cstc2022ycjh-bgzxm0184//Chongqing Talent Plan/ ; CSTC2021jscx-gksb-N0020//Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund/ ; 2021ZD0201802//STI2030-Major Projects/ ; 2018YFC2001700//National Key R&D Program of China/ ; 0201[2023]160 202412//Chongqing Medical Key Discipline and Regional Medical Key Discipline Development Project/ ; },
mesh = {Humans ; Male ; *Alzheimer Disease/microbiology/physiopathology/therapy/blood ; Female ; *Cognition/physiology ; Aged ; *Methylamines/blood/metabolism ; *Down-Regulation ; Gastrointestinal Microbiome ; Cognitive Dysfunction/physiopathology ; Cognitive Training ; },
abstract = {BACKGROUND: The microbiota-gut-brain (MGB) axis is implicated in Alzheimer's disease (AD), but evidence for interventional strategies targeting this axis remains limited.

METHODS: In a 24-week, single-blind, randomized controlled trial, 84 individuals with mild cognitive impairment (MCI) or mild AD received either computerized cognitive training (CCT) or treatment as usual (TAU). Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was the primary outcome. We also assessed functional connectivity (fNIRS), plasma trimethylamine N-oxide (TMAO) levels, and gut microbiota at baseline and 24 weeks.

RESULTS: Seventy-four participants completed the study. The CCT group showed significant improvement in ADAS-cog scores compared to controls (Cohen's d = 1.57 by week 24). Notably, CCT also induced a distinct reorganization of prefrontal functional connectivity and significantly reduced plasma TMAO levels. Microbiome analysis revealed that CCT mitigated the expansion of Ruminococcus torques group (R.torques), which was observed in the control group. Crucially, R.torques was the only genus significantly correlated with improvements in cognition (ADAS-cog, r = 0.407), neuropsychiatric symptoms (NPI, r = 0.395), TMAO reduction (r = 0.443), and functional connectivity changes (r = 0.449).

CONCLUSION: A 24-week CCT program improves cognitive function in MCI and mild AD, potentially through downregulating the R.torques-TMAO pathway within the MGB axis. This pathway represents a promising novel target for multi-domain intervention in AD.},
}

Humans
Male
*Alzheimer Disease/microbiology/physiopathology/therapy/blood
Female
*Cognition/physiology
Aged
*Methylamines/blood/metabolism
*Down-Regulation
Gastrointestinal Microbiome
Cognitive Dysfunction/physiopathology
Cognitive Training

@article {pmid41136359,
year = {2025},
author = {Pan, X and Su, Z and Huang, Z and Chen, Y and Li, X and Zheng, X},
title = {N-acetylcysteine (NAC) ameliorates ethanol-induced oxidative stress, neuroinflammation, and cognitive dysfunction in APP/PS1 mouse model.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {435},
pmid = {41136359},
issn = {2158-3188},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Ethanol/toxicity/adverse effects ; Mice ; *Oxidative Stress/drug effects ; Disease Models, Animal ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroinflammatory Diseases/chemically induced/drug therapy ; Mice, Transgenic ; Male ; Microglia/drug effects ; *Antioxidants/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; Disks Large Homolog 4 Protein/metabolism/drug effects ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder that predominantly affects the elderly, leading to a progressive decline in cognitive function. Accumulating evidence suggests that many environmental and dietary factors, especially chronic ethanol exposure, aggravate the risk of this disease. However, its precise influence on AD has not yet been clarified. Here, we show that ethanol exposure caused earlier and severer cognitive behavioral impairments, more beta amyloid (Aβ) depositions, microglia activation, decreased total antioxidant capacity (T-AOC). Moreover, inflammatory mediators, such as Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and Tumor necrosis factor-alpha (TNF-α) increased, while pivotal proteins involved in dendritic and synaptic development, such as Synaptophysin (SYP), postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) decreased in APP/PS1 mice. N-acetylcysteine (NAC), a well-known antioxidant, could attenuate cognitive behavioral impairments and neuroinflammatory damage by restoring inflammatory and neurodevelopmental mediators. In general, our study uncovered that chronic ethanol exposure may exacerbate AD progress at the pathological and molecular levels and NAC may act as a potential drug for the treatment of AD patients with chronic ethanol exposure.},
}

Animals
*Acetylcysteine/pharmacology
*Ethanol/toxicity/adverse effects
Mice
*Oxidative Stress/drug effects
Disease Models, Animal
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Alzheimer Disease/drug therapy/metabolism
*Neuroinflammatory Diseases/chemically induced/drug therapy
Mice, Transgenic
Male
Microglia/drug effects
*Antioxidants/pharmacology
Brain-Derived Neurotrophic Factor/metabolism/drug effects
Amyloid beta-Peptides/metabolism
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects
Disks Large Homolog 4 Protein/metabolism/drug effects
Amyloid beta-Protein Precursor/genetics

@article {pmid41135777,
year = {2025},
author = {Zhang, S and Fan, Z and Ji, D},
title = {Advances in eye-brain axis: anatomy, immunity, and association with visual dysfunction.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102925},
doi = {10.1016/j.arr.2025.102925},
pmid = {41135777},
issn = {1872-9649},
abstract = {The "eye-brain axis" refers to the dynamic system of interactions between the eyes and the brain, collectively encompassing the visual signal transmission and integration pathways. The eyes and the brain exhibit structural and functional synergy, and visual dysfunction not only impairs information processing within the eye but also induces structural and functional remodeling of the central nervous system (CNS) via the eye-brain axis. For instance, the effects of glaucoma on the visual cortex are manifested as reduced blood perfusion and decreased efficiency of mitochondrial adenosine triphosphate (ATP) synthesis. Moreover, the eye can serve as an important window and biomarker for the early diagnosis and intervention of neurodegenerative diseases of the CNS. Relevant research findings include the parallelism of beta amyloid (Aβ) and phosphorylated Tau (p-Tau) between the retina and Alzheimer's disease (AD), glaucomatous neurodegeneration with AD-like features, and the role of vascular endothelial growth factor C (VEGF-C) expression along the eye-brain lymphatic pathway in regulating intraocular pressure (IOP) and correcting macular edema. Therefore, eye-brain axis research provides novel perspectives for understanding the pathophysiological mechanisms underlying visual dysfunction and related disorders, while simultaneously supporting the development of cross-organ neuroprotective strategies. This review explores the anatomical foundations, immune regulation, and bidirectional interactions of the eye-brain axis, and evaluates its relevance to the diagnosis and treatment of visual dysfunction and degenerative diseases of the CNS.},
}

@article {pmid41135742,
year = {2025},
author = {Hu, T and Xi, J and Xie, N and Zhang, X and Huang, N and Cheng, Y},
title = {Multi-Omics Analysis Reveals the Protective Role of Transcriptional Enhancer Factor and the Pathogenic Mechanism of Monocytes in Parkinson's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111594},
doi = {10.1016/j.brainresbull.2025.111594},
pmid = {41135742},
issn = {1873-2747},
abstract = {Parkinson's disease (PD) is a multifactorial neurodegenerative disorder whose pathogenic mechanisms remain incompletely elucidated. This study aimed to systematically identify key regulatory factors involved in PD at the genetic, cellular, and molecular levels. Using univariate Mendelian randomization (UVMR), we identified plasma proteins and genes associated with Alzheimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS), and validated their causal relationships through colocalization analysis. Cross-validation across multi-omics datasets revealed transcriptional enhancer factor (TEF) as a protective factor for PD, whereas increased counts of CD14[+]CD16[+] monocytes were identified as a risk factor. Single-cell analysis and multivariate Mendelian randomization (MVMR) further suggested potential mediating roles of these factors in PD pathogenesis. In vitro experiments demonstrated that TEF overexpression significantly enhanced the resistance of neuroblastoma cells to rotenone-induced damage, inhibited apoptosis, and preserved tyrosine hydroxylase (TH) expression. In vivo, TEF notably improved motor coordination and exploratory behavior in PD mouse models. Collectively, these findings suggest that TEF may exert neuroprotective effects by modulating immune and neuronal pathways, offering a novel therapeutic target for the prevention and treatment of Parkinson's disease.},
}

@article {pmid41134994,
year = {2025},
author = {Mullins, CA and Gannaban, RB and Kramer, A and Shah, H and Haque, ZF and Ramezan, M and Dehghani, F and Palaniyappan, AK and Bowers, F and MohanKumar, SM and MohanKumar, PS and Shin, AC},
title = {Early branched-chain amino acid reduction delays the onset of cognitive decline in a mouse model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389236},
doi = {10.1177/13872877251389236},
pmid = {41134994},
issn = {1875-8908},
abstract = {BackgroundMany Alzheimer's disease (AD) treatments focus on a single variable of AD that have yet demonstrated clinically meaningful and perceived benefits by the patients. We recently showed that lowering plasma branched-chain amino acids (BCAAs) can deliver multiple pro-neuronal effects in APP/PS1 and 5xFAD mouse models.ObjectiveThe main aim was to determine the optimal point in time for the disease-modifying effects of BCAA reduction during AD development.Methods12-month-old, cognitively impaired male WT and APP/PS1 mice were injected with either vehicle or BCAA-lowering compound BT2 (40 mg/kg/day ip) for 30 days. To test if early BT2 during AD progression would have long-lasting beneficial effects, 2-month-old, cognitively intact male 5xFAD mice were treated with BT2 after which they were left alone for a month.ResultsPlasma BCAAs were reduced in BT2-treated APP/PS1 mice. Despite Aβ42 reduction, BT2 did not modify proteins or genes related to AD-related pathology, dendritic density and neurotransmitters in the cortex and hippocampus, or alleviate cognitive deficit. In another experiment, BT2-treated 5xFAD mice had lower plasma BCAAs. Importantly, early BT2, even after treatment cessation for a month, was able to effectively delay cognitive impairment which was associated with a complete restoration of cortical neurotransmitters. These results were observed without any changes in pathology markers in the brain.ConclusionsOur findings suggest that BT2-induced BCAA reduction is a novel strategy to delay AD progression possibly through enhanced neurotransmission. The efficacy is time-dependent such that treating with BT2 before the onset of AD can successfully rescue cognitive function.},
}

@article {pmid41134991,
year = {2025},
author = {Tseng, P},
title = {Does weak gamma entrainment still work? Rethinking the comfort-efficacy trade-off in 40 Hz sensory stimulation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389153},
doi = {10.1177/13872877251389153},
pmid = {41134991},
issn = {1875-8908},
abstract = {As 40 Hz sensory stimulation gains attention as a potential treatment for Alzheimer's disease, comfort-focused designs such as invisible spectral flicker and multi-luminaire are increasingly used to promote long-term compliance. However, these systems often produce significantly weaker electroencephalographic entrainment than traditional stroboscopic lights. It is therefore important to question the common assumption that any level of entrainment is sufficient, and consider the possibility of nonlinear or threshold-based mechanisms that may require a minimum entrainment strength for therapeutic effects. The field needs to empirically test the relationship between entrainment strength and outcome, to ensure efficacy is not compromised for comfort.},
}

@article {pmid41134085,
year = {2025},
author = {Xu, YJ and Wu, T and Lo, LT and Ko, CC and Wang, X and Ma, CHE},
title = {Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e05421},
doi = {10.1002/advs.202505421},
pmid = {41134085},
issn = {2198-3844},
support = {ITS/099/23FP//Innovation and Technology Commission of the Hong Kong Special Administrative Region (HKSAR) Government/ ; R1005-24F//Research Grant Council of the HKSAR Government/ ; CityU11100424//Research Grant Council of the HKSAR Government/ ; 08193956//Health and Medical Research Fund, Food and Health Bureau, HKSAR Government/ ; 32400807//National Natural Science Foundation of China/ ; },
abstract = {Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H4R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H4R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD.},
}

@article {pmid41133841,
year = {2025},
author = {Yao, L and Ni, J and Wei, M and Li, T and Li, F and Wang, T and Xiao, W and Shi, J and Tian, J},
title = {Recent Advances in the Application of Artificial Intelligence in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050410489250930175402},
pmid = {41133841},
issn = {1875-5828},
abstract = {Artificial intelligence (AI) refers to a system that can simulate and execute the processes of human thinking and learning, and make informed decisions. Fueled by the development of AI, the quality and effectiveness of medical work have gained momentum. AI technology plays an increasingly important role in healthcare, exhibiting substantial potential in clinical practice and decision-making processes. In Alzheimer's disease (AD), where early diagnosis and treatment remain challenging due to clinical heterogeneity and insidious progression, AI could offer excellent solutions. AI models can integrate multi-modal data to identify pre-symptomatic biomarkers and stratify high-risk cohorts, improving diagnostic accuracy, assisting with personalizing treatment and care. Furthermore, AI can accelerate drug discovery and development through drug-target identification and predictive modeling of compound efficacy. However, data quality, supervision, transparency, privacy, and ethical concerns need to be addressed. By identifying and retrieving studies for the systematic review, this article provides a comprehensive overview of current progress and related AI applications in AD.},
}

@article {pmid41133228,
year = {2025},
author = {Wang, S and Shi, Y and Xin, R and Kang, H and Xiong, H and Ren, J},
title = {Exploring the role of insulin resistance in bridging the metabolic syndrome and Alzheimer's disease-a review of mechanistic studies.},
journal = {Frontiers in endocrinology},
volume = {16},
number = {},
pages = {1614006},
pmid = {41133228},
issn = {1664-2392},
mesh = {*Insulin Resistance/physiology ; Humans ; *Alzheimer Disease/metabolism/pathology/etiology ; *Metabolic Syndrome/metabolism/pathology ; Animals ; Oxidative Stress ; Renin-Angiotensin System ; },
abstract = {The association between metabolic syndrome (MetS) and Alzheimer's disease (AD) has attracted widespread attention; nevertheless, the precise mechanism of action between the two is not yet fully elucidated. This review systematically explores the complex mechanisms of insulin resistance (IR) in MetS and AD. We first detail the intrinsic mechanisms of insulin resistance and emphasize its central role in the pathophysiology of MetS. Further, we reveal the underlying mechanisms by which insulin resistance in turn triggers AD through a multidimensional pathway that promotes the accumulation of pathological products, induces blood-brain barrier dysfunction, impairs neuroplasticity, induces neuroinflammatory responses, aberrantly activates the renin-angiotensin-aldosterone system, and exacerbates oxidative stress. In addition, we summarize potential strategies for targeting IR in AD treatment and demonstrate the promising prospects for improving insulin resistance in promoting cognitive recovery. This study offers a novel theoretical framework for elucidating the intricate relationship between MetS and AD. Furthermore, it provides a scientific foundation for the formulation of preventive and therapeutic strategies for metabolic and neurodegenerative diseases.},
}

*Insulin Resistance/physiology
Humans
*Alzheimer Disease/metabolism/pathology/etiology
*Metabolic Syndrome/metabolism/pathology
Animals
Oxidative Stress
Renin-Angiotensin System

@article {pmid41132583,
year = {2025},
author = {Zou, Z and Lei, D and Wang, X and Yin, Y and Li, H and Di, X and Li, X},
title = {Crocin Ameliorates Cognitive Impairment and Pathological Changes in Alzheimer's Disease Model Mice by Regulating Gut Microbiota.},
journal = {Food science & nutrition},
volume = {13},
number = {10},
pages = {e71117},
pmid = {41132583},
issn = {2048-7177},
abstract = {Alzheimer's disease (AD), a primary cause of dementia, places a significant strain on both patients and society due to the absence of effective treatments. Recent research suggests that the gut microbiota may play a role in the development of AD. Crocin, a compound derived from traditional medicine, has demonstrated potential in alleviating neurological disorders and influencing gut microbiota, yet its specific mechanisms in AD remain unclear. In this study, we administered Crocin or saline to 5xFAD mice and wild-type controls. We discovered that Crocin treatment led to notable improvements in cognitive function, as measured by the Morris water maze test, reduced beta-amyloid (Aβ) accumulation, and decreased neuroinflammation, as indicated by reduced microglial and astrocyte activation. Metagenomic sequencing revealed a significant increase in the gut microbiota diversity, specifically the abundance of Firmicutes, Verrucomicrobiota, and Akkermansia. Additionally, Crocin enhanced intestinal barrier function by upregulating tight junction proteins and Secretory immunoglobulin A, while improving the structure of the jejunal mucosa. These results suggest that Crocin may alleviate cognitive deficits and neuropathological changes in 5xFAD mice, possibly through modulation of the gut microbiota and strengthening the gut barrier, presenting it as a promising therapeutic approach for AD.},
}

@article {pmid41132573,
year = {2025},
author = {Sriramcharan, P and Ahmed, SS and Natarajan, J and Kumar, RR and Antony, J and Kumar, AP and Anjali, PB and Ganganagappa, N and Shah, RM and Madar, IH},
title = {Cerium oxide nanoparticles synthesized via green route exhibit neuroprotective effects in Alzheimer's-induced Albino Wistar rats.},
journal = {3 Biotech},
volume = {15},
number = {11},
pages = {398},
pmid = {41132573},
issn = {2190-572X},
abstract = {UNLABELLED: Green synthesis of cerium oxide nanoparticles emerges as a feasible therapeutic strategy for disorders like Alzheimer's to determine its antioxidant and cytotoxicity in the in vitro environment, following in vivo studies, safety and effectiveness were confirmed. This approach has gained increased reliability compared to physical and chemical methods due to its non-toxic and environmentally friendly nature. The synthesized nanoparticles are then characterized using Fourier transform infrared spectrometry (FTIR), particle size, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman spectroscopy. Design optimization was applied to the selected variables to get the best-fit values of the experiment. FTIR spectroscopy revealed amide, carboxyl, and ester groups in the cerium oxide particles produced by Candida albicans, indicating their significance in nanoparticle stabilization. The particle size and zeta potential of cerium oxide nanoparticles were found to be 152 nm and - 15 mV, respectively. Various antioxidant studies, such as 2, 2-Diphenyl-2-Picryl Hydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS), anti-lipid peroxidation, and catalase, were conducted, revealing that synthesized nanoparticles had high antioxidant activity. SEM images produced high-quality, evenly distributed images. Cerium oxide nanoparticles effectively inhibited SK-N-SH human neuroblastoma cells, with an IC50 value of 65 µg/ml. An in vivo study was performed using an amyloid-beta-induced intracerebroventricular rat model. The finding demonstrates the induction of AD in rats led to spatial memory impairments, whereas the treatment with cerium oxide nanoparticles suggests a significant improvement in neuroprotective effect. This outcome was validated through Morris water maze behavioral assessment and histopathological analysis. The results indicated that the synthesized cerium oxide nanoparticles, optimizing using the Box-Behnken design, resulted in strong antioxidant and cytotoxic activities (65%).

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04563-4.},
}

@article {pmid41131967,
year = {2025},
author = {Javed, A and Mandal, P and Khan, I and Singh, A and Akhtar, J and Maheshwari, S and Prajapati, BG},
title = {Liposomal Drug Delivery for Neurological Disorders: Advances and Challenges.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {25},
number = {3},
pages = {245-260},
pmid = {41131967},
issn = {1875-6166},
mesh = {Humans ; *Liposomes/chemistry/administration & dosage/metabolism ; *Drug Delivery Systems/methods/trends ; *Nervous System Diseases/drug therapy/metabolism ; Animals ; Blood-Brain Barrier/drug effects/metabolism ; *Neuroprotective Agents/administration & dosage ; },
abstract = {Liposomal drug delivery methods are becoming increasingly viable options for improving treatment outcomes for neurological illnesses. These systems provide a flexible framework for the formulation of medications intended for delivery to the brain, protecting the medication from enzymatic breakdown and enhancing its bioavailability. To maximize liposome-drug interactions and improve brain-targeted delivery efficiency, a variety of formulation strategies are used, such as surface modification and remote loading. By utilizing various pathways to cross the blood- -brain barrier (BBB), such as passive diffusion and receptor-mediated transcytosis, liposomes facilitate the effective transport of therapeutic drugs to the brain parenchyma. Liposomal formulations show potential for targeted drug delivery, reducing off-target effects, and improving treatment efficacy in neurological conditions like Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis, and brain cancers. For instance, in Parkinson's disease, liposomal delivery of neuroprotective agents can help maintain dopamine levels and protect dopaminergic neurons. In Alzheimer's disease, liposomes can be engineered to deliver drugs that reduce amyloid-beta plaques or tau tangles. For brain cancer, liposomal chemotherapy can target tumor cells more precisely while minimizing damage to surrounding healthy tissue. In stroke, liposomal delivery of neuroprotective agents can reduce the extent of brain damage, while in multiple sclerosis, liposomes can be used to deliver drugs that modulate the immune response. However, the clinical translation of liposomal drug delivery systems for brain diseases faces challenges related to scalability, stability, and immunogenicity, in addition to regulatory barriers. Scalability issues arise from the complex manufacturing processes required to produce liposomes consistently on a large scale. Stability concerns involve maintaining the integrity of liposomes during storage and after administration. Immunogenicity can be a problem if the liposomes trigger an unwanted immune response, potentially reducing their effectiveness or causing adverse effects. To overcome these obstacles, multidisciplinary cooperation is essential. Collaboration among materials scientists, pharmacologists, neurologists, and regulatory experts can drive the development of more robust liposomal formulations. Continuous research is needed to refine liposome designs, such as by optimizing lipid composition, surface charge, and size to improve stability and targeting capabilities. Advanced techniques like PEGylation (coating liposomes with polyethylene glycol) can help reduce immunogenicity and extend circulation time in the bloodstream. Despite these challenges, liposomal methods present intriguing prospects for transforming medication administration to the brain and offering effective treatments for neurological illnesses. The development of more sophisticated liposomal technologies, combined with a deeper understanding of their mechanisms of action, could lead to significant breakthroughs in the treatment of neurological disorders. For example, research into ligand- targeted liposomes, which use specific molecules to bind to receptors on the BBB, holds promise for enhancing delivery specificity and efficiency. To fully realize the therapeutic promise of these novel drug delivery systems, further advancements in liposomal technologies and a deeper understanding of their mechanisms are necessary. This includes not only technical improvements but also comprehensive preclinical and clinical studies to evaluate safety, efficacy, and long-term effects. As our knowledge expands and technology progresses, liposomal drug delivery could become a cornerstone of neurological disease treatment, providing new hope for patients with previously intractable conditions.},
}

Humans
*Liposomes/chemistry/administration & dosage/metabolism
*Drug Delivery Systems/methods/trends
*Nervous System Diseases/drug therapy/metabolism
Animals
Blood-Brain Barrier/drug effects/metabolism
*Neuroprotective Agents/administration & dosage

@article {pmid41131557,
year = {2025},
author = {Buchanan, RA and Kramer, AT and Calipari, ES and Bowman, AB and Nobis, WP and Harrison, FE},
title = {Differential impact of manganese on glutamate clearance, electroencephalography, and sleep in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70821},
doi = {10.1002/alz.70821},
pmid = {41131557},
issn = {1552-5279},
support = {DK135073/DK/NIDDK NIH HHS/United States ; DK020593/DK/NIDDK NIH HHS/United States ; //FEH and ABB/ ; T32 ES007028/ES/NIEHS NIH HHS/United States ; P50 HD103537/HD/NICHD NIH HHS/United States ; HD103537//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01 ES031401/ES/NIEHS NIH HHS/United States ; R01 ES035518/ES/NIEHS NIH HHS/United States ; ES007028/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Manganese/toxicity/metabolism/pharmacology ; Electroencephalography ; *Glutamic Acid/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Sleep/drug effects ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; *Brain/drug effects/metabolism ; Mice, Inbred C57BL ; },
abstract = {INTRODUCTION: Underlying glutamate dysregulation in Alzheimer's disease can be worsened by environmental factors like manganese (Mn) exposure. This study examined how excess Mn affects glutamatergic signaling and neurotransmission in a beta-amyloid mouse model.

METHODS: APP/PSEN1 and control mice were exposed to systemic Mn subcutaneously. Gene expression, glutamate clearance dynamics, electroencephalography (EEG) activity, and sleep architecture were analyzed using quantitative polymerase chain reaction (qPCR), Western blot, ex vivo hippocampal slices, and EEG recordings.

RESULTS: Mn exposure elevated brain Mn levels and altered glutamate dynamics in both WT and APP/PSEN1 mice. Wild-type (WT) mice showed faster glutamate clearance, increased spiking, disrupted sleep, and brain wave changes. APP/PSEN1 mice exhibited slower glutamate clearance, altered gene expression, increased glial fibrillary acidic protein (GFAP), and changes in non-rapid eye movement (NREM) delta and rapid eye movement (REM) alpha power.

DISCUSSION: Mn exposure altered glutamate clearance and brain activity, particularly in WT mice. APP/PSEN1 mice showed impaired clearance, limited gene expression changes, and altered EEG patterns, suggesting distinct or pre-existing compensatory mechanisms.

HIGHLIGHTS: Manganese exposure significantly alters glutamate clearance dynamics differentially in wild-type and APP/PSEN1 mouse models of Alzheimer's disease. Acute manganese treatment disrupts sleep architecture, evidenced by changes in electroencephalography (EEG) patterns and vigilance states. APP/PSEN1 mice exhibit slower glutamate clearance and altered gene expression compared to wild-type mice following manganese exposure. Distinct brain wave frequency shifts were observed in response to manganese treatment, particularly affecting delta, theta, and alpha rhythms. Findings suggest a potential exacerbation of excitatory/inhibitory imbalances due to environmental manganese exposure in Alzheimer's pathology.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Manganese/toxicity/metabolism/pharmacology
Electroencephalography
*Glutamic Acid/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
*Sleep/drug effects
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Male
*Brain/drug effects/metabolism
Mice, Inbred C57BL

@article {pmid41129981,
year = {2025},
author = {Wang, B and Chang, Y and Shen, L and Ma, Y and Zhang, Z and Du, J and Wang, Y and Li, Y and Zhao, F and Wang, J and Pang, X and Fan, W and Du, L and Yan, L},
title = {Multifunctional near-infrared fluorescent probe for imaging of hydrogen peroxide and photodynamic therapy of amyloid-β aggregation in Alzheimer's disease.},
journal = {Talanta},
volume = {298},
number = {Pt B},
pages = {129009},
doi = {10.1016/j.talanta.2025.129009},
pmid = {41129981},
issn = {1873-3573},
abstract = {Photodynamic therapy (PDT) has shown significant potential in eliminating amyloid-β (Aβ) aggregates, the characteristic pathological marker of Alzheimer's disease (AD). However, traditional photosensitizers have limitations such as off-target oxidation and single functionality, which severely hinder their specificity and therapeutic efficiency in clearing Aβ plaques. Given the complexity of AD's pathological mechanisms, the development of novel photosensitizers with both targeting ability and multifunctionality has become an urgent priority. In this study, a H2O2-responsive near-infrared (NIR) fluorescent probe ENBS-P was designed and synthesized. By integrating the dual functions of H2O2 visualization and precise photodynamic therapy, it has achieved efficient application in both in vitro and in vivo models. ENBS-P could be specifically activated by H2O2 to release ENBS, resulting in a significant enhancement of fluorescence signal at 720 nm (λex = 640 nm), thus realizing highly sensitive in situ detection of H2O2 (LOD = 0.2 μM). In addition, benefiting from a more efficient intersystem crossing (ISC) process from S1 to T1, the therapeutic molecule ENBS, generated after the specific activation of ENBS-P by H2O2, could produce superoxide radical anions (O2[-•], Type I photoreaction) under NIR light excitation. Importantly, through imaging-guided PDT, it could effectively inhibit the aberrant aggregation of Aβ42 and promote the dissociation of formed aggregates. This study overcomes the limitations of traditional photosensitizers by providing an innovative "diagnosis-treatment" integrated strategy for the early diagnosis and therapy of AD, holding significant promise for advancing precision medicine in AD.},
}

@article {pmid41129661,
year = {2025},
author = {Wu, CS and Huang, WL and Wang, SH and Wu, MS and Chen, KS and Cheng, SH and Chiu, YM},
title = {Association Between Autoimmune Diseases, Treatments, and Dementia Risk: A Population-Based Case-Control Study From Taiwan.},
journal = {The Journal of clinical psychiatry},
volume = {86},
number = {4},
pages = {},
doi = {10.4088/JCP.25m15774},
pmid = {41129661},
issn = {1555-2101},
mesh = {Humans ; Taiwan/epidemiology ; Female ; Male ; *Autoimmune Diseases/epidemiology/drug therapy/complications ; *Dementia/epidemiology/etiology ; Middle Aged ; Aged ; Case-Control Studies ; Comorbidity ; Prevalence ; Aged, 80 and over ; Risk Factors ; Immunosuppressive Agents/therapeutic use ; },
abstract = {Objectives: This study aimed to assess the risk of dementia associated with specific autoimmune diseases and the impact of related pharmacologic treatments. Methods: Patients 55 years or older diagnosed with dementia by neurologists or psychiatrists between 2010 and 2021 were identified using claims data from Taiwan's National Health Insurance program. We examined 22 autoimmune diseases for their associations with dementia, controlling for age, gender, urbanization level, and comorbidities. Results: Dementia prevalence was higher among individuals with autoimmune diseases (10.5% in cases vs. 8.7% in comparisons). Thirteen autoimmune diseases were linked with an elevated dementia risk, particularly Behçet disease, multiple sclerosis, and systemic lupus erythematosus. Associations with vascular dementia were stronger than with Alzheimer disease. Although overall dementia risk was higher in women, no significant sex differences were observed for specific autoimmune diseases. Nonsteroidal anti-inflammatory drugs and corticosteroids did not significantly alter dementia risk among individuals with autoimmune diseases; however, immunosuppressants were associated with a reduced risk when used for more than 180 days. Conclusions: Certain autoimmune diseases are significantly associated with an increased risk of dementia, particularly vascular dementia, highlighting the distinct role of inflammation. Effective prevention or treatment of autoimmune diseases may reduce dementia incidence by 0.8%. While immunosuppressants show potential for risk reduction, further prospective studies are needed to confirm this effect.},
}

Humans
Taiwan/epidemiology
Female
Male
*Autoimmune Diseases/epidemiology/drug therapy/complications
*Dementia/epidemiology/etiology
Middle Aged
Aged
Case-Control Studies
Comorbidity
Prevalence
Aged, 80 and over
Risk Factors
Immunosuppressive Agents/therapeutic use

@article {pmid41128826,
year = {2025},
author = {Hoveizi, E and Bijavi, G and Parsa, H},
title = {Advancing Cell Therapy to Enhance Passive Avoidance Memory: Integrative Approaches Combining Neural-Like Cells and Rosmarinic Acid Through Behavioral, Molecular, and Histological Analyses.},
journal = {Neurochemical research},
volume = {50},
number = {6},
pages = {334},
pmid = {41128826},
issn = {1573-6903},
mesh = {Animals ; Rosmarinic Acid ; *Depsides/pharmacology/therapeutic use ; *Cinnamates/pharmacology/therapeutic use ; Male ; *Alzheimer Disease/therapy/metabolism/pathology ; Rats ; *Avoidance Learning/physiology/drug effects ; *Cell- and Tissue-Based Therapy/methods ; *Memory/physiology/drug effects ; Mesenchymal Stem Cells/cytology ; Rats, Sprague-Dawley ; *Neurons/drug effects/metabolism ; Cell Differentiation/physiology/drug effects ; Dental Pulp/cytology ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration, synaptic dysfunction, and cognitive decline. Regenerative strategies aim to replace lost neurons and modulate the inflammatory milieu to restore neural networks. This study examined the effects of neural-like cells (NLCs) derived from dental pulp mesenchymal stem cells (DPSCs) on a chitosan scaffold using rosmarinic acid (RA) in AD rats. In this study, DPSCs were extracted from teeth, characterized and differentiated, induced an AD model by destroying the Meynert nucleus, conducted passive avoidance tests, analyzed histology and immunohistochemistry, and measured inflammatory and oxidative stress markers. The extraction and differentiation of DPSCs were successful. Differentiated DPSCs into neural progenitors showed increased expression of Tuj-1, Map2, Nestin, and NF (RT-PCR, p < 0.001). Behavioral tests confirmed the AD model after seven days, and histology showed neuronal loss and gliosis following Meynert destruction. Histomorphology revealed improved brain tissue and significantly increased choline acetyltransferase (ChAT) expression in the treatment groups. Notable behavioral improvements were observed in the Y‑maze and shuttle box for treated rats compared with the AD group. Biochemical analyses showed a significant decrease in inflammatory markers IL‑1β, IL‑6, and TNF‑α, along with increases in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) in the RA-treated groups. The results provide reliable evidence that DPSCs, in combination with RA, exert a promising therapeutic effect and represent a meaningful advance toward the clinical application of combination therapies for patients with AD.},
}

Animals
Rosmarinic Acid
*Depsides/pharmacology/therapeutic use
*Cinnamates/pharmacology/therapeutic use
Male
*Alzheimer Disease/therapy/metabolism/pathology
Rats
*Avoidance Learning/physiology/drug effects
*Cell- and Tissue-Based Therapy/methods
*Memory/physiology/drug effects
Mesenchymal Stem Cells/cytology
Rats, Sprague-Dawley
*Neurons/drug effects/metabolism
Cell Differentiation/physiology/drug effects
Dental Pulp/cytology
Oxidative Stress/drug effects

@article {pmid41127243,
year = {2025},
author = {Li, G and Li, S and Zhou, W},
title = {Kynurenine pathway: a possible new mechanism for exercise in the prevention and treatment of Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1617690},
pmid = {41127243},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease in clinical practice. The kynurenine pathway (KP) is a potential intersection of factors associated with the development of AD (central nervous inflammation, glutamate excitotoxicity, and tau phosphorylation, among others). Pharmacological modulators targeting KP enzymes, such as inhibitors or agonists, and their major neuroprotective metabolites are beneficial in alleviating AD progression. Exercise significantly improves AD symptoms and also impacts KP pharmacokinetics. Promoting the production of neuroprotective active metabolites by KP may be one of the central mechanisms by which exercise improves AD symptoms. This article reviews the possible role of KP in AD neurodegeneration and AD exercise prevention and treatment.},
}

@article {pmid41126950,
year = {2025},
author = {Frost, B and Kolb, H and Algeciras-Schimnich, A and Betthauser, TJ and DeVos, S and Edelmayer, RM and Elwood, F and Fleisher, AS and Henley, D and Horie, K and Hyman, B and Kreisl, WC and Kulic, L and Leuzy, A and Palma, JA and Parmentier-Batteur, S and Patru, MM and Rabinovici, GD and Reyderman, L and Sperling, RA and Van Der Geyten, S and Wildsmith, KR and Mahinrad, S and Carrillo, MC and Weber, CJ},
title = {Tau biology, biomarkers, and therapeutics.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70165},
pmid = {41126950},
issn = {2352-8737},
abstract = {UNLABELLED: As Alzheimer's disease (AD) research advances, tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. The Fall 2024 Alzheimer's Association Research Roundtable convened experts from academia, industry, National Institutes of Health (NIH), and the United States Food and Drug Administration (FDA) to explore current progress and future directions in tau-centered diagnostics and therapeutics. Discussions addressed the integration of tau biomarkers into the 2024 Revised Diagnostic Criteria for AD, updates to amyloid and tau positron emission tomography (PET) imaging, and modeling of biomarker trajectories. Presenters highlighted tau-targeting therapeutics including antisense oligonucleotides, monoclonal antibodies, and small molecules, alongside innovations in drug delivery. The interplay between anti-amyloid and anti-tau therapies and strategic design of combination trials were key themes. Regulatory insights facilitated discussions on drug approval pathways. The meeting highlighted the rapid evolution of tau research and emphasized opportunities to improve diagnostics, trial design, and treatment strategies in AD.

HIGHLIGHTS: The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to explore current progress and future directions in tau-centered diagnostics and therapeutics.Tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development.Discussions addressed the integration of tau biomarkers into the 2024 revised diagnostic criteria for AD, updates to amyloid and tau PET imaging, modeling of biomarker trajectories, tau-targeting therapeutics, and interplay between anti-amyloid and anti-tau therapies and strategic design of combination trials.},
}

@article {pmid41126823,
year = {2025},
author = {Atkinson, J and Dokiburra, A and Groover, H and Godbout, JP and Segal, BM and Zhang, Y},
title = {Targeting senescent microglia in progressive multiple sclerosis: a geroscience-informed approach.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1681724},
pmid = {41126823},
issn = {1664-3224},
mesh = {Animals ; *Microglia/drug effects/pathology/metabolism/immunology ; Mice ; *Encephalomyelitis, Autoimmune, Experimental/drug therapy/immunology/pathology ; *Cellular Senescence/drug effects ; Humans ; *Multiple Sclerosis/drug therapy/pathology ; *Senotherapeutics/pharmacology/therapeutic use ; Female ; Disease Models, Animal ; Senescence-Associated Secretory Phenotype/drug effects ; *Multiple Sclerosis, Chronic Progressive/drug therapy/pathology ; Mice, Inbred C57BL ; },
abstract = {Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disorder of the central nervous system (CNS). Age is the strongest predictor of disease phenotype, with the majority of older adults transitioning to a progressive form marked by irreversible neurological decline. This clinical progression is associated with smoldering, CNS-compartmentalized inflammation and neurodegeneration, for which there are currently no effective disease-modifying therapies. Cellular senescence, characterized by the secretion of pro-inflammatory mediators collectively known as the senescence-associated secretory phenotype (SASP), increases with age and contributes to tissue injury. In MS, neuroinflammation can further promote cellular senescence, creating a self-reinforcing cycle of damage. Senescent microglia have been identified within MS lesions, where their SASP may impair remyelination and exacerbate neurodegeneration. Senolytic agents selectively target and eliminate senescent cells by disrupting anti-apoptotic pathways. In experimental autoimmune encephalomyelitis (EAE), a widely used model of MS, senolytic treatment reduces senescent microglia burden and attenuates disease severity in an age- and drug-dependent manner. Specifically, here we show that middle-aged mice (40-44 weeks) with EAE exhibit improved clinical outcomes and survival following treatment with either dasatinib plus quercetin (D+Q) or navitoclax. Early-phase clinical trials of senolytics in age-related diseases have demonstrated functional benefits, including improved gait speed in idiopathic pulmonary fibrosis and CNS penetrance in Alzheimer's disease. Translating senolytic therapy to MS will require careful selection of CNS-penetrant and well-tolerated agents, identification of appropriate patient populations, and deployment of responsive biomarkers. Senolytic therapy represents a promising geroscience-based strategy to meet the urgent therapeutic need in progressive MS.},
}

Animals
*Microglia/drug effects/pathology/metabolism/immunology
Mice
*Encephalomyelitis, Autoimmune, Experimental/drug therapy/immunology/pathology
*Cellular Senescence/drug effects
Humans
*Multiple Sclerosis/drug therapy/pathology
*Senotherapeutics/pharmacology/therapeutic use
Female
Disease Models, Animal
Senescence-Associated Secretory Phenotype/drug effects
*Multiple Sclerosis, Chronic Progressive/drug therapy/pathology
Mice, Inbred C57BL

@article {pmid41126448,
year = {2025},
author = {Biel, D and Steward, A and Dewenter, A and Dehsarvi, A and Zhu, Z and Roemer-Cassiano, SN and Frontzkowski, L and Hirsch, F and Palleis, C and Höglinger, G and Brendel, M and Franzmeier, N and , },
title = {A systematic comparison of ATN biomarkers for monitoring longitudinal cognitive changes in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70783},
doi = {10.1002/alz.70783},
pmid = {41126448},
issn = {1552-5279},
support = {EXC2145SyNergy-ID390857198//Munich Cluster for Systems Neurology/ ; AARG-22-973496/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Biomarkers/blood ; *tau Proteins/blood ; Positron-Emission Tomography ; Male ; Female ; Longitudinal Studies ; Aged ; Magnetic Resonance Imaging ; Amyloid beta-Peptides ; Aged, 80 and over ; *Cognitive Dysfunction/diagnostic imaging ; Brain/diagnostic imaging/pathology ; Cognition ; },
abstract = {INTRODUCTION: With anti-amyloid beta (Aβ) therapies approved for Alzheimer's disease (AD), surrogate biomarkers are needed to monitor clinical treatment efficacy. Therefore, we systematically compared longitudinal changes in A/T/N biomarkers (amyloid-positron emission tomography [PET], tau-PET, plasma phosphorylated tau at threonine 217 [p-tau217], and magnetic resonance imaging) for tracking cognitive changes.

METHODS: We analyzed longitudinal biomarker and cognitive change rates from the Alzheimer's Disease Neuroimaging Initiative (N = 141) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (N = 151), estimated using linear mixed models. Using linear models, we tested biomarker changes as predictors of cognitive changes, comparing predictive strengths across biomarkers using bootstrapping.

RESULTS: Tau-PET, plasma p-tau217, and cortical thickness changes accurately tracked change rates in Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive Subscale 13-item version, Clinical Dementia Rating-Sum of Boxes, and Preclinial Alzheimer Cognitive Composite scores. In contrast, amyloid-PET change rates were not linked to cognitive changes.

DISCUSSION: Plasma p-tau217 offers a cost-effective AD-specific alternative to tau-PET and could potentially be implemented for monitoring cognitive changes in AD trials, while amyloid-PET lacks utility. Cortical thickness changes accurately track cognitive changes but may be confounded by pseudo-atrophy in anti-Aβ treatments.

HIGHLIGHTS: Longitudinal changes in tau-PET, plasma p-tau217, cortical thickness - but not amyloid-PET - effectively track cognitive decline. Cortical thickness may be confounded by pseudo-atrophy in anti-Aβ trials. Plasma p-tau217 is a robust and cost-effective alternative to tau-PET as an AD-specific surrogate biomarker for monitoring cognitive changes.},
}

Humans
*Alzheimer Disease/diagnostic imaging
*Biomarkers/blood
*tau Proteins/blood
Positron-Emission Tomography
Male
Female
Longitudinal Studies
Aged
Magnetic Resonance Imaging
Amyloid beta-Peptides
Aged, 80 and over
*Cognitive Dysfunction/diagnostic imaging
Brain/diagnostic imaging/pathology
Cognition

@article {pmid41126430,
year = {2025},
author = {Alhawarri, MB},
title = {Hypothesis-Driven Insights and Clinical Trial Updates in Alzheimer's Disease Pathogenesis.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273387383250924031644},
pmid = {41126430},
issn = {1996-3181},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the primary cause of dementia and a significant threat to healthy aging. The prevalence of AD and other non-communicable diseases (NCDs) is significantly influenced by the progressive decline in physiological functions that is associated with aging.

METHODS: This review summarizes the results of drug interventions for AD that have been conducted in the past five years, with a particular emphasis on Phase I, Phase III, and Phase IV clinical trials. Systematic investigations of clinical trial registries and databases were employed to identify clinical trials. A total of 106 Phase I, 52 Phase III, and 13 Phase IV trials were considered, excluding studies on devices, biologics, and diagnostic tests.

RESULTS: This review summarizes a wide range of therapy approaches aimed at different facets of AD pathogenesis, including amyloid-beta aggregation, tau protein dysfunction, neuroinflammation, synapse loss, and metabolic dysregulation. AD's complex nature highlights the need for multi-target treatment strategies, which may encompass combination therapies and innovative targets that show potential in addressing the complex pathogenesis of AD.

DISCUSSION: Current clinical studies demonstrate a variety of therapies aimed at various pathogenic processes of AD. Progress in therapeutic discovery, including synthetic molecules and bioactive natural materials, suggests potential strategies for successful AD treatment. The efficacy of natural products as therapeutic agents is especially significant because of their multi-target effects.

CONCLUSION: Effective strategies to prevent the progression of AD require a thorough comprehension of its complex pathophysiology. Current clinical studies are essential for discovering viable chemicals and treatment strategies to combat this multifactorial neurodegenerative disorder, AD.},
}